DESIGN AND EVALUATION OF A NON-OPIOID TRIPARTITE RELEASE TABLET FOR 

CHRONIC INFLAMMATORY PAIN. 

 

KUNDAI ROSELYN MAZARURA 

 

 

 

 

 

 

 

A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, 

in fulfilment of the requirements for the degree of Master of Pharmacy 

 

Supervisor 

 Prof. Yahya E. Choonara 

Department of Pharmacy and Pharmacology, University of the Witwatersrand, South Africa 

 

Co-Supervisors 

Prof. Pradeep Kumar 

Department of Pharmacy and Pharmacology, University of the Witwatersrand, South Africa 

 

Dr. Armorel van Eyk 

Department of Pharmacy and Pharmacology, University of the Witwatersrand, South Africa 

 

 

2024



 
ii 

 

DECLARATION 

 

I, Mazarura R. Kundai, declare that this dissertation is my own work. It has been submitted for 

the degree of Master of Pharmacy in the Faculty of Health Sciences at the University of the 

Witwatersrand, Johannesburg, South Africa. It has not been submitted before for any degree 

or examination at this or any other University. 

 

This 16th day of April 2024. 

 

 

 

X
Kundai Mazarura

Ms

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 
iii 

 

PUBLICATION 

 

Kundai R. Mazarura, Pradeep Kumar & Yahya E. Choonara (2022): Customized 3D printed 

multi-drug systems: an effective and efficient approach to polypharmacy, Expert Opinion on 

Drug Delivery, DOI: 10.1080/17425247.2022.2121816                                                             

To link to this article: https://doi.org/10.1080/17425247.2022.2121816  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

https://doi.org/10.1080/17425247.2022.2121816


 
iv 

 

ABSTRACT 

 

 

Formulation-based approaches towards curbing the prescription opioid crisis include the 
discovery and development of non-opioid analgesics such as the novel benzyloxy-
cyclopentyladenosine (BnOCPA). A more expedited approach involves the development of 
combinatorial systems of already existing non-addicting analgesics to tap into unexplored 
synergistic potentials. Despite the recent advances in drug delivery systems, tablets still hold 
the position of being the most widely used oral dosage form, particularly in the management 
of chronic ailments; it is cost-effective, non-invasive, and does not require administration 
expertise.  

Challenges in the production of complex geometry combinatorial, multi-drug tablets remain to 
some extent enigmatic to pharmaceutical researchers, hence the steady paradigm shift from 
traditional compression to 3-dimensional printing. Although it is superior in multiple aspects, 
the technique is still in its nascent stages with limited information on regulatory guidelines. 
Therefore, the aim of this work was to design and develop a non-opioid tripartite controlled-
release tablet for efficient chronic inflammatory pain management. Because adherence to 
adjunct gastroprotective agents (GPAs) in non-steroidal anti-inflammatory drugs (NSAIDs) 
users has been established to be suboptimal, esomeprazole magnesium trihydrate (ESM) was 
added to the drug delivery system (DDS). The rationale behind the design was based on 
inherent drug properties, target release sites, desired therapeutic effects, and allowance for 
drug release manipulation, therefore a tablet was assembled, constituting an immediate-
release top layer formulation of 250 mg paracetamol (PAR) for an early onset of analgesia; a 
cup layer for the delayed and retarded release of 100 mg of diclofenac sodium (DS) and 250 
mg of PAR in tandem, and lastly a core containing a press-coated 20 mg ESM pill. 

A reproducible and efficient Reverse-Phase High-Performance Liquid Chromatographic (RP-
HPLC) method was developed and validated for the simultaneous detection of the APIs over 
the concentration ranges studied. Deleterious drug-excipient incompatibilities were ruled out 
through pre-formulation investigations by FTIR, DSC, and TGA analyses. Combining both wet 
and dry granulation methodologies; the chosen formulation and polymers (7.5% hydroxypropyl 
methylcellulose (HPMC) K15M, 25.3% eudagrit L (EL) 100-55, and 10.5% croscarmellose 
sodium (CCS)), while considering the quality target product profiles (QTPPs), critical process 
parameters (CPP), and critical material attributes (CMAs), resulted in the development of a 
pragmatic tablet delivering fifty percent of the PAR dosage in the initial 30 minutes, with a 
cumulative release of 95.0% ± 0.08% and 94.9% ±3.87% for DS and ESM, respectively. 

Through in-process quality control tests, the validity of the manufacturing process was 
confirmed, with all results falling within pharmacopeial specifications. The release mechanism 
of PAR and DS from the cup after the 2-hour mark distinctly followed the Hixson-Crowell model 
where the geometrical characteristic of the cup was maintained with surface erosion. Visuals 
from scanning electron microscopy (SEM) analysis obtained prior to and during dissolution, 
confirmed hydration gravimetric analysis results as well as bulk and surface erosion 
mechanisms. The obtained ex vivo analysis results showed retarded permeation rates of the 
tabletted APIs compared to the APIs in their pure state. Therefore, it is imperative to consider 
improving the existing models employed for ex-vivo permeability studies of tableted 
formulations, with a particular focus on exploring the impact of excipients/polymers on drug 
permeation. 

 

 



 
v 

 

ACKNOWLEDGEMENTS 

 

My sincere appreciation goes to my esteemed supervisors for not only their invaluable support 

and supervision but also for entrusting me with this project and allowing me to live out my 

passion for medicine manufacturing. Through their redirections and solutions, drawn from their 

immense knowledge pools and experience I managed to see the project to the end.  

I also want to thank the WADDP researchers for creating an environment that is conducive to 

research, inspiring, and positively influential in every way, with specific acknowledgment of 

Ahmed Abdelgader for generously sharing his expertise on the operation of the tablet press 

machine and much more.  

Despite having a limited understanding of what this stage of my academic path entailed, my 

parents were highly supportive in every way possible, for which I am exceedingly grateful. I'd 

want to thank my friends and brother Tapiwa Mazarura, (fellow academics) who brought joy 

to what could have been a lonely 2-3 years of my life.  

The 2023 academic year would not have been possible without the scholarship I received from 

MINDS; my thanks go to them as well. 

Above all, I thank God the Father, Son, and Holy Spirit, “in whom I live and move and have 

my being." I thank Him for keeping me safe in the late-night hours on the days the research 

demanded it. 

 

 

 

 

 

 

 

 

 

 

 



 
vi 

 

DEDICATION 

 

 

 

 

 

 

 

 

 

 

 

 

 

This work is dedicated to my late grandfathers, my paternal grandfather, who treasured 

knowledge acquisition even in his old age, and my maternal grandfather, who died in pain 

in 2021 with the conviction that I could make him a magical pill with no side effects to 

alleviate his pain. 

 

 

 

 

 

 

 

 

 

 

 

 

 



 
vii 

 

TABLE OF CONTENTS 

 

DECLARATION ......................................................................................................................ii 

PUBLICATION ...................................................................................................................... iii 

ABSTRACT ........................................................................................................................... iv 

ACKNOWLEDGEMENTS ..................................................................................................... v 

DEDICATION ........................................................................................................................ vi 

TABLE OF CONTENTS ....................................................................................................... vii 

LIST OF FIGURES............................................................................................................... xii 

LIST OF TABLES ................................................................................................................. xv 

LIST OF ABBREVIATIONS ................................................................................................ xvii 

 

CHAPTER 1 

INTRODUCTION AND MOTIVATION FOR THE STUDY 

1.1 Background ................................................................................................................. 1 

1.2 Rationale Behind the Design and Combination ............................................................ 3 

1.3 Aims and Objectives of the Study. ................................................................................ 5 

1.4 Overview of This Dissertation ...................................................................................... 6 

 

CHAPTER 2 

LITERATURE REVIEW ON NOVEL FORMULATION TECHNIQUES FOR CONTROLLED 

RELEASE MULTI-DRUG SYSTEMS 

2.1 Introduction .................................................................................................................. 8 

2.2 Summary on 3D Printing Technologies ...................................................................... 10 

2.3 Customisation in Different Population Groups............................................................ 11 

2.3.1 Visually Impaired Patients ................................................................................... 11 

2.3.2 Paediatric Patients .............................................................................................. 12 

2.3.3 Geriatric Patients ................................................................................................. 12 

2.4 3D Printed Multi-Drug Dosage Forms ........................................................................ 13 

2.4.1 3D Printed Oral Multi-Drug Formulations ............................................................. 13 

2.4.1.1 Formulations Printed by Fused Deposition Modelling ................................... 13 

2.4.1.2 Formulations Printed by Pressure Assisted Microsyringe Extrusion .............. 16 



 
viii 

 

2.4.1.3 Formulations Printed by Stereolithography ................................................... 17 

2.4.1.4 Formulations Printed by Selective Laser Sintering .......................................  17 

2.4.2 3D Printed Multi-Drug Eluting Implants ................................................................ 20 

2.5 Additive Materials Used in 3D Printing of Multi-Drug Systems ................................... 21 

2.5.1 Other High Functionality Polymers ...................................................................... 25 

2.6 Limitations and Barriers to Implementation ................................................................ 25 

2.6.1 Regulatory Constraints ........................................................................................ 25 

2.6.2 Processing Parameters ....................................................................................... 26 

2.6.2.2 Printer Accuracy ........................................................................................... 26 

2.6.2.3 Return on Investment (ROI) .......................................................................... 26 

2.7 Cost Implications and Projected Market Views .......................................................... 27 

2.8 Conclusion ................................................................................................................. 28 

2.9 Expert Opinion ........................................................................................................... 30 

 

CHAPTER 32 

PRE-FORMULATION INVESTIGATIONS AND LIQUID CHROMATOGRAPHIC METHOD 

DEVELOPMENT AND VALIDATION FOR THE SIMULTANEOUS QUANTITATION OF THE 

ACTIVE INGREDIENTS 

3.1 Introduction ................................................................................................................ 32 

3.2 Materials and methods .............................................................................................. 33 

3.2.1 Materials ............................................................................................................. 33 

3.2.2 Fourier Transform Infrared Spectroscopic Analysis ............................................. 34 

3.2.3 Differential Scanning Calorimetry Analysis .......................................................... 34 

3.2.4 Thermogravimetry Analysis ................................................................................. 34 

3.2.5 HPLC Method Development and Validation ........................................................ 34 

3.2.5.1 Wavelength Selection ................................................................................... 35 

3.2.5.2 Method Development and Optimization ........................................................ 36 

3.2.5.3 Method Validation ......................................................................................... 36 

3.2.5.3.1 Preparation of Standards ....................................................................... 36 

3.2.5.3.2 Linearity, LOD, and LOQ Determination ................................................. 36 



 
ix 

 

3.2.5.3.3 Method Precision Analysis ..................................................................... 37 

3.2.5.3.4 Specificity Analysis ................................................................................. 37 

3.2.5.3.5 Accuracy Analysis .................................................................................. 38 

3.2.5.3.6 Robustness Analysis .............................................................................. 38 

3.2.5.3.7 Stability Analysis .................................................................................... 38 

3.3 Results ...................................................................................................................... 39 

3.3.1 FTIR Analysis ...................................................................................................... 39 

3.3.2 DSC and TGA Analysis ....................................................................................... 40 

3.3.3 Method Development and Validation ................................................................... 42 

3.3.3.1 Method Development .................................................................................... 42 

3.3.3.2 Method Validation ......................................................................................... 43 

3.3.3.2.1 Linearity, LOD, and LOQ ............................................................................ 43 

3.3.3.2.2 Method Precision and Accuracy ............................................................. 45 

3.3.3.2.3 Robustness Analysis .............................................................................. 46 

3.3.3.2.4 Stability Analysis .................................................................................... 47 

3.3.3.2.5 Specificity/Selectivity Analysis ................................................................ 48 

3.4 Conclusion ................................................................................................................. 48 

 

CHAPTER 4 

FORMULATION DEVELOPMENT AND COMPARATIVE IN VITRO DRUG RELEASE 

ANALYSIS 

4.1 Introduction ................................................................................................................ 50 

4.2 Materials and Methods .............................................................................................. 52 

4.2.1 Materials ............................................................................................................. 52 

4.2.2 Formulation Development ................................................................................... 52 

4.2.3 Pre-Compression Evaluation ............................................................................... 55 

4.2.4 Assemblage of the Full DDS ............................................................................... 56 

4.2.5 In Vitro Drug Release Studies ............................................................................. 56 

4.3 Results ...................................................................................................................... 57 

4.3.1 Pre-Compression Powder Flow Analysis ............................................................. 57 



 
x 

 

4.3.2 Dissolution results and influence of polymers ...................................................... 58 

4.3.2.1 IR Layer: Influence of CCS and PVP-K30 Concentrations ............................ 58 

4.3.2.2 DR Cup ......................................................................................................... 59 

4.3.2.3 Core and Plug Efficiency ............................................................................... 62 

4.4 Conclusion ................................................................................................................. 65 

 

CHAPTER 5 

IN-PROCESS EVALUATION POST-COMPRESSION ANALYSIS AND 

CHARACTERISATION OF THE FINAL FORMULATION 

5.1 Introduction ................................................................................................................ 66 

5.2 Materials and Methods .............................................................................................. 68 

5.2.1 Materials ............................................................................................................. 68 

5.2.2 Preparation of the Drug Delivery System ............................................................ 68 

5.2.3 In-Process Quality Control Evaluation ................................................................. 70 

5.2.4 Indentation Hardness Test .................................................................................. 70 

5.2.5 Gravimetric Analysis Through Water Uptake and Erosion Studies ...................... 71 

5.2.6 Determination of polymeric structural variations using Fourier Transmission 

Infrared spectroscopy .................................................................................................. 72 

5.2.7 Determination of the thermal behaviour ............................................................... 72 

5.2.8 Determination of surface morphology using Scanning Electron Microscopy ........ 72 

5.2.9 In Vitro Drug Release Analysis ............................................................................ 73 

5.3 Results ...................................................................................................................... 73 

5.3.1 In-Process Quality Control Evaluation ................................................................. 73 

5.3.2 Indentation Hardness Test .................................................................................. 74 

5.3.3 Gravimetric Analysis ........................................................................................... 74 

5.3.4 Polymeric Structural Variations Analysis ............................................................. 75 

5.3.5 Determination of the Thermal Behaviour ............................................................. 76 

5.3.6 Determination of Surface Morphology Using Scanning Electron Microscopy ....... 78 

5.3.7 In Vitro Drug Release Analysis ............................................................................ 80 

5.4 Conclusion ................................................................................................................. 83 



 
xi 

 

CHAPTER 6 

EX VIVO PERMEABILITY ANALYSIS OF THE DRUG DELIVERY SYSTEM ACROSS 

PORCINE DUODENAL TISSUE 

6.1 Introduction ................................................................................................................ 84 

6. 2 Material and Methods ............................................................................................... 87 

6.2.1 Materials ............................................................................................................. 87 

6.2.2 Tissue Isolation and Preparation ......................................................................... 87 

6.2.3 Sample Preparation and Experiment Set-Up ....................................................... 88 

6.2.4 Analysis of Permeants......................................................................................... 89 

6.2.4.1 HPLC Quantification ..................................................................................... 89 

6.2.4.2 Permeability Calculations.............................................................................. 89 

6.2.5 Integrity Analysis of the Intestinal Mucosa ........................................................... 90 

6.3 Results and Discussion ............................................................................................. 90 

6.3.1 Permeation Characteristics Analysis ................................................................... 90 

6.3.2 Integrity Analysis ................................................................................................. 94 

6.4 Conclusion ................................................................................................................. 95 

 

CHAPTER 7 

CONCLUSION AND RECOMMENDATIONS 

7.1 Conclusion ................................................................................................................. 96 

7.2 Recommendations ..................................................................................................... 97 

 

REFERENCES ................................................................................................................... 98 

 

APPENDICES................................................................................................................... 126 

Appendix 1: Abstract of Review Paper ........................................................................... 126 

Appendix 2: Ethics Waiver Certificate ............................................................................ 127 

Appendix 3: Permeability Regression Lines and Cumulative Amount Formula .............. 128 

 

 



 
xii 

 

LIST OF FIGURES 

Figure 1.1: Molecular mechanisms that mediate PGE2-induced pain hypersensitivity 

inflammation. (A) COX-2 and mPGES-1 are upregulated in both injured cells and infiltrating 

immune cells in inflamed tissues, which increases PGE2 concentrations at peripheral 

nociceptor terminals. (B) Inflammation upregulates COX-2 and mPGES-1 expression in the 

spinal cord and increases PGE2 production. PGE2, mainly acting on EP2 receptors, 

contributes to central sensitization through both presynaptic and post-synaptic mechanisms..

 ............................................................................................................................................. 2 

Figure 1.2: Core-in-Cup PDDS.. ............................................................................................ 3 

Figure 1.3: Schematic of the ideal desired release profiles.................................................... 5 

Figure 2.1: Schematic diagram of the Digital Micromirror Device (DMD) stereolithography 

(DLP 3DP) setup including designs and images of 3D printed theophylline tablets. ............ 11 

Figure 2.2: Comparison between mass-produced conventional dosage forms-based therapy 

and 3D printing-based personalized therapy. ...................................................................... 12 

Figure 2.3: a. HME coupled FDM 3D printing procedure without in-line PAT tools b. HME 

coupled FDM 3D printing with PAT tools.............................................................................. 15 

Figure 2.4: Selected images of 3D printed multi-drug system configurations.. ..................... 19 

Figure 2.5: Picture of the self-assembly of HA and PQ-10 and the fibrous PECs collected by 

filtration before drying. SEM image of 3D printed FDC,alongside prolonged drug release 

profiles of a) Efavirenz (EFV), b) Tenofovir Disoproxil Fumarate (TDF) and c) Emtricitabine 

(FTC) in comparison to the commercial version, Atripla®. .................................................... 23 

Figure 3.1: Chemical structures of a. PAR, b. ESM c. DS. ................................................... 33 

Figure 3.2: Overlain spectra of the three actives obtained by UV-Vis Spectrophotometric 

analysis. .............................................................................................................................. 35 

Figure 3.3: FTIR spectra of individual APIs (PAR, DS, ESM), key polymers (HPMC E50LV, 

HPMC K15M, MCC, EL 100-55), and potential API and polymer combinations as per 

fomulation layers (left to right). ............................................................................................ 40 

Figure 3.4: DSC thermograms of individual APIs, key polymers, and potential combinations 

(above and below). ............................................................................................................. 42 

Figure 3.5: TGA curves of individual APIs and key polymers. .............................................. 42 



 
xiii 

 

Figure 3.6: Regression lines and respective representative chromatograms showing the 

retention of a.PAR at 1.916 min, b.DS at 6.716 min, and c.ESM at 5.940 min. .................... 44 

Figure 3.7: Chromatogram showing the retention of PAR at 1.863 min, ESM at 5.807 min, 

and DS at 6.803 min in a combined sample containing 1 mg/ml of each drug (1:1:1). ......... 46 

Figure 3.8: Specificity chromatograms of a. the Mobile Phase b. Excipients and c. APIs + 

Excipients in the ratio 25:5:1 (125:25:5 µg/ml).. .................................................................. 48 

Figure 4.1: Summarisation of the QbD principles applied in the development of the present 

DDS. ................................................................................................................................... 51 

Figure 4.2: Schematic representatives of preliminary drug delivery systems for segregated 

investigation of each layer. . ................................................................................................ 56 

Figure 4.3: IR-Layer drug release profiles in SGF pH 1.2 (n=3; %RSD < 2.00 in all cases). 59 

Figure 4.4: a. PAR b. DS DR Cup Layer drug release profiles in SGF pH 1.2 (0 – 2 hours), 

SSIF pH 6.8 (2 – 10 hours) (n=3; %RSD < 5.00 in all cases). ............................................. 61 

Figure 4.5: a. Uncoated, showing early gastric release of ESM b. coated drug release 

profiles in SGF pH 1.2 (0 – 2 hours), SSIF pH 6.8 (2 hours onwards) (n=3; 5.00 < %RSD < 

10.00 for a., %RSD < 5.00 for b.. ........................................................................................ 64 

Figure 4.6: Digital visuals of formulation components during dissolution analysis, at pH 1.2 

for after the first 2 hours. ..................................................................................................... 65 

Figure 5.1: Polymeric controlled-release mechanisms. Schematic Illustration Of (A) Solvent-

Activated and Stimuli-Responsive Systems. (i) The swelling-controlled system shows drug 

diffusion through the expandable hydrogel. (ii) The designed orifice in an osmotic-controlled 

system lets drug molecules release out with an adjustable release rate. (iii) External physical 

stimuli activate the responsive polymeric carriers to release their cargo in a controllable 

manner. (B) Chemically mediated CRSs. (i) Detachment of drug molecules from pendant 

side-chain polymeric systems (ii) Bulk erosion (iii) Surface versus mechanisms through 

erodible systems.. ............................................................................................................... 68 

Figure 5.2: Presentation of a. Uncoated and Press-Coated ESM Core Pills; and overall 

manufacturing procedure. ................................................................................................... 69 

Figure 5.3: Typical Force (N) versus Distance (mm) profile generated for the calculation of 

BHN values. ........................................................................................................................ 71 

Figure 5.4: Digital images of a. the tablet b. Digital Calliper measurements of tablet 
dimensions, c. F1, showing the difference in thickness. ...................................................... 73 

Figure 5.5: Mass gain and loss profiles of the tablets as a function of time. ........................ 75 



 
xiv 

 

Figure 5.6: FTIR spectra of individual APIS and respective tablet formulation layers........... 76 

Figure 5.7: TGA thermograms for APIs and respective tablet formulation layers. ................ 77 

Figure 5.8: DSC thermograms for separate tablet formulation layers. ................................. 78 

Figure 5.9: SEM Images of the core contents a. Surface view of the press coat, b. cross-

sectional view of the ESM pill, c. Cross-sectional view 2 hours into dissolution in SGF, and d. 

4 hours into dissolution in SSIF. In all cases, magnification was 200 X, except for b (500 X) 

at 5 kV. ................................................................................................................................ 79 

Figure 5.9.1: a. b. SEM images of the IR layer at 200X and 2kX, respectively before 

dissolution, c. DR cup surface morphology before dissolution, d. 2 hours, and e. 4 hours into 

dissolution in SGF and SSIF, respectively, at 200X magnification at 5kV. ............................ 79 

Figure 5.9.2: Cumulative drug release profiles in both SGF and SSIF (n=3) of a. F1 with 

respective overlain chromatograms showing the retention and detection of i. PAR only from 

samples withdrawn within the first 2 hours of dissolution and ii. ESM and DS from 2 hours 

onwards, b. F2 c. F3. Total Cumulative Amount Released, F1 PAR 101.09 % ± 0.80; DS 

95,55 % ± 1.46; ESM 93.60 % ± 1.21. F2 101.81 % ±0.28; DS 9.71% ±1.39, ESM 82.43 % ± 

3.16, and F3 PAR 101.53% ± 0.51; DS 95.46 % ± 0.70; ESM 95.07% ±3.89.  .................... 82 

Figure 6.1: a. Oblique view of Franz Cell, b. Oblique view of Side-by-Side Cell, and c. 

Everted gut sac apparatus with dimensions a. and complete setup b.. ................................ 86 

Figure 6.2: Cross-sectional view of an in-line cell with HPLC fittings. .................................. 86 

Figure 6.3: Digital Images of a. Specimen collection from euthanised white female pig and b. 

tissue preparation. .............................................................................................................. 88 

Figure 6.4: Digital image of the Franz-Diffusion apparatus setup utilised for penetration 

analysis. .............................................................................................................................. 88 

Figure 6.5: Cumulative permeation plots of a. PAR, b. DS, c. ESM in and out of formulation, 

d. Combined Tablet Plot (n=3). ............................................................................................ 93 

Figure 6.6: FTIR spectra of porcine duodenal tissue, pre- and post-exposure ..................... 94 

Figure 6.7: Graphical correlation plot of fraction absorbed versus apparent permeability 

coefficients of compounds observed in many higher throughput pharmacokinetic assays.. . 95 

 



 
xv 

 

LIST OF TABLES 

 

Table 2.1: Summary of 3D Printed multi-drug oral dosage forms. ........................................ 18 

Table 2.2: 3D Printed multi-drug implants. ........................................................................... 21 

Table 3.1: Integral, Onset and Endset temperature values for the individual API, excipient, 

and combined samples. ...................................................................................................... 41 

Table 3.2: Summary of Reverse Phase RP-HPLC conditions applied. ................................ 43 

Table 3.3: Summary of regression statistics, LOD and LOQ values for the APIs. ................ 43 

Table 3.4: Summary of precision results (n=3). ................................................................... 45 

Table 3.5: Summary of accuracy results on standards (n=3) ............................................... 45 

Table 3.6: Summary of accuracy results on tablet formulation dilution (n=3). ...................... 46 

Table 3.7: Summary of robustness assessment (n=3). ........................................................ 47 

Table 3.8: Stability assessment on standards (n=3 injections). ............................................ 47 

Table 4.1:  Immediate Release Layer formulation composition. ........................................... 53 

Table 4.2:  Delayed Release Cup layer formulation composition. ........................................ 54 

Table 4.3: Core formulation composition. ............................................................................ 54 

Table 4.4: Plug formulation. ................................................................................................. 54 

Table 4.5: Core Press Coat composition. ............................................................................ 55 

Table 4.6: Scale of flowability determined by different methods. .......................................... 56 

Table 4.7: Constituents of dissolution media. ...................................................................... 57 

Table 4.8: Flow properties per formulation granules. ........................................................... 58 

Table 4.9:  Best of fit values: IR Layer (n=3). ....................................................................... 59 

Table 4.9.1: a. Best of fit values with Tlag: DR Layer (PAR). ............................................... 62 

Table 4.9.1: b. Best of fit values with Tlag: DR Layer (DS). ................................................. 62 

Table 4.9.2: Best of fit values with Tlag: ESM. ..................................................................... 64 

Table 5.1: Risk estimation matrix presenting initial risk assessment levels of the drug delivery 

system formulation and manufacturing parameters. ............................................................ 67 

Table 5.2: Resultant formulations. ....................................................................................... 69 



 
xvi 

 

Table 5.3: Texture Analyser settings applied. ....................................................................... 71 

Table 5.4: Summary of results from in-process validation tests on tablets ± SD. ................. 74 

Table 5.5: Mean DSC integration data (n=3 samples). ........................................................ 77 

Table 5.6: Best of fit values for the different kinetic models. ................................................ 82 

Table 6.1a: Flux rates and permeability coefficients as determined through ex vivo 

permeation analysis. ........................................................................................................... 93 

Table 6.1b: Flux rates and permeability coefficients as determined through ex vivo 

permeation analysis (in formulation). ................................................................................... 94 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



 
xvii 

 

LIST OF ABBREVIATIONS 

 

3DP  3 Dimensional Printed  

4IR  4th Industrial Revolution 

ABS  Acrylonitrile Butadiene Styrene 

ACN  Acetonitrile 

APIs  Active Pharmaceutical Ingredients 

ATR-FTIR Attenuated Total Reflectance-Fourier Transform Infrared 

BCS  Biopharmaceutics Classification System 

BHN  Brinell Hardness Number 

BIJ  Binder Ink Jetting 

BnOCPA Benzyloxy-cyclopentyladenosine 

CAGR  Compound Annual Growth Rate 

CCS  Croscarmellose Sodium 

CMAs  Critical Material Attributes 

COX  Cyclooxygenase 

CPOP  Controlled Porosity Osmotic Pump 

CPPs  Critical Process Parameters 

CQAs  Critical Quality Attributes 

DDSs  Drug-Delivery Systems 

DIW  Direct Ink Writing  

DLP  Digital Light Processing 

DMD  Digital Micro-Mirror Device 

DPPO  Diphenyl (2,4,6-Trimethylbenzoyl)-Phosphine Oxide  

DR  Delayed Release 

DS  Diclofenac Sodium 

DSC  Differential Scanning Calorimetry 

EC  Ethyl Cellulose 

EL                   Eudragit L 

EFV  Efavirenz 

ESM  Esomeprazole Magnesium Tri-Hydrate 

EVA  Ethylene Vinyl Acetate 

EXT  Extrusion (at room Temperature) 



 
xviii 

 

FDA  Food and Drug Administration 

FDC  Franz Diffusion Cell 

FDM  Fused Deposition Modelling 

FTC  Emtricitabine 

FTIR  Fourier Transform Infrared Spectroscopy 

GIT  Gastrointestinal Tract 

GPAs  Gastroprotective Agents 

HME  Hot Melt-Extrusion 

HPC  Hydroxypropyl Cellulose 

HPMC  Hydroxypropyl Methylcellulose 

ICH  International Conference Harmonization 

IMP  Impregnation 

INH  Isoniazid 

IPQC  In-Process Quality Control  

IR  Immediate release 

LD  Levodopa 

LOD  Limit of Detection 

LOQ  Limit of Quantification 

MCC  Microcrystalline 

NaCMC           Sodium carboxymethylcellulose 

NSAIDs Non-Steroidal Anti-Inflammatory Drugs 

ODT  Orally Disintegrating Tablet 

PAM  Pressure Assisted Microsyringe 

PAR  Paracetamol 

PAT  Process Analytical Technology 

PBPK  Physiologic-Based Pharmacokinetic 

PBS  Phosphate Buffered Saline  

PCL  Poly Ɛ-Caprolactone 

PDDS  Pulsatile Drug Delivery Systems 

PDLA  Poly D-Lactic Acid 

PDLLA  Poly-D,L-Lactic Acid  

PEC  Polyelectrolyte Complexes 

PEEK  Polyether Ether Ketone  

PEKK  Polyether Ketone 



 
xix 

 

PEO  Polyethylene Oxide 

PGE2  Prostaglandin (E2) 

PLA  Polylactic Acid 

PLLA  Poly-L-Lactic Acid 

PoC  Point-Of-Care 

PPIs  Proton Pump Inhibitor 

PVA  Polyvinyl Alcohol  

PVP  Polyvinylpyrrolidone 

QbD  Quality by Design 

QbT  Quality by Testing 

QTPP  Quality Target Product Profile 

RP-HPLC Reverse Phase-High Performance Liquid Chromatography 

RSD                Relative Standard Deviation 

SEM  Scanning Electron Microscopy 

SFF  Solid Freeform Technology 

SGF  Simulated Gastric Fluid 

SLA  Stereolithography  

SLM  Selective Laser Melting 

SLS  Selective Laser Sintering  

SLS                 Sodium Lauryl Sulphate  

SMEDDS Self-Micro Emulsifying Drug Delivery Systems 

SNEDDS Self-Nanoemulsifying Drug Delivery Systems 

SR  Sustained Release 

SSG  Sodium Starch Glycolate 

SSIF  Simulated Small Intestinal Fluid 

TDF  Tenofovir Disoproxil Fumarate 

TGA  Thermogravimetric Analysis 

TLC  Thin Layer Chromatography 

UPLC-MS Ultra-Performance Liquid Chromatography-Mass Spectrometry 

UV                   Ultra-Violet Visible 

WHO  World Health Organisation



 
1 

 

CHAPTER 1 

INTRODUCTION AND MOTIVATION FOR THE STUDY 

1.1 Background 

An ongoing conundrum for healthcare professionals has been how to effectively manage 

chronic pain without posing risks of tolerance, dependence, and addiction, with nearly 1 in 

every 5 South Africans suffering from chronic pain, limbic joint pain, and back pain making up 

43.6%, and 30.5% of the pain, respectively (Kamerman et al., 2020). The range of available 

pharmacological treatment options for long-term management is predominantly restricted to 

non-steroidal anti-inflammatory drugs (NSAIDs) and/or opioid analgesics. Frequently, patients 

choose opioids as their preferred choice due to their well-established effectiveness in pain 

relief and occasional mood-altering benefits (Engel-Rebitzer et al., 2021; Dowel et al., 2022; 

Seidel et al., 2022; Castle et al., 2023). Of late, rising rates of opioid overdose deaths have 

raised questions about prescribing opioids for chronic pain management. Worldwide, about 

0.5 million deaths are attributable to drug use of which more than 70% of these deaths are 

related to opioids, with more than 30% of those deaths being a result of overdose. Because 

of the risk of serious harm, without sufficient evidence for benefits, current guidelines 

discourage opioid prescribing for chronic pain (Dowel et al., 2022). “Opioid misuse and abuse 

remain a serious public health crisis facing the country. Preventing new addiction through 

fostering the development of novel non-opioid analgesics is an important priority for the FDA,” 

Patrizia Cavazzoni, M.D., director of the FDA’s Centre for Drug Evaluation and Research 

(FDA, 2022).  

The pathophysiology of persistent inflammatory pain commonly found in joint diseases 

includes signalling initiated by peripheral terminals of sensory neurons (Chen, Yang and 

Grosser, 2013; Seidel et al., 2022). The presence of algogens such as prostaglandins, 

particularly E2 (PGE2), in the synovium and synovial fluid capable of exciting or sensitizing 

peripheral nociceptors, describes the generation of pain in inflammatory joint diseases. PGE2 

is a product of the hydrolysis of arachidonic acid, a reaction catalysed by cyclooxygenase 

enzyme 2 (COX-2) (Di Carlo, Smerilli and Salaffi, 2021), Figure 1.1. The pathophysiology 

explains the rationale behind the use of COX inhibitors in associated conditions. On the other 

hand, inhibition in the synthesis of prostaglandins in patients on chronic Non-Steroidal Anti-

Inflammatory Drugs (NSAIDs) induces clinically significant ulceration, bleeding, and/or 

obstruction.  The pathogenesis of NSAID-induced ulceration and bleeding involves three key 

pathways: inhibition of cyclooxygenase (COX)-1 activity, inhibition of COX-2 activity, and direct 

cytotoxic effects on the epithelium (Wallace, 2008). Selective COX-2 inhibitors were at some 



 
2 

 

point hailed for their non-ulcer-inducing mechanism due to their COX-1 sparing pathway until 

the role of the COX-2 pathway was identified in the pathogenesis of NSAID-induced damage, 

including evidence of increased risks of myocardial infarction to the point of withdrawal from 

general use. Therefore, regardless of the NSAID of choice, concomitant proton pump inhibitor 

(PPIs) co-therapy is crucial. There exists comprehensive evidence on the effectiveness of 

PPIs over standard doses of H2 receptor antagonists and that they are as effective as, but 

better tolerated than misoprostol in ulcer prophylaxis (Rancis et al., 2002; Dieppe, Shah 

Ebrahim and Jüni, 2004; Wallace, 2008; Lazzaroni and Porro, 2009). 

 

Figure 1.1: Molecular mechanisms that mediate PGE2-induced pain hypersensitivity 
inflammation. (A) COX-2 and mPGES-1 are upregulated in both injured cells and infiltrating 
immune cells in inflamed tissues, which increases PGE2 concentrations at peripheral 
nociceptor terminals. (B) Inflammation upregulates COX-2 and mPGES-1 expression in the 
spinal cord and increases PGE2 production. PGE2, mainly acting on EP2 receptors, 
contributes to central sensitization through both presynaptic and post-synaptic mechanisms. 
Modified and reprinted with permission from   (Chen, Yang and Grosser, 2013). 

The tablet remains the go-to dosage form in most pharmaceutical developments due to its 

plethora of advantages, particularly in chronic disease management (Hummler et al., 2023). 

Controlled pulsatile-release multi-drug solid oral dosage forms have been instrumental in 

treating various chronic ailments improving adherence and compliance patterns in most 

patients (Huynh and Lee, 2015). Pulsatile drug delivery systems (PDDS), i.e., systems in 

which the drug is released suddenly after a well-defined lag time according to the circadian 

rhythm of the disease, are classified as either, time-controlled pulsatile release (single or 

multiple unit system), internal stimuli-induced or external stimuli-induced release systems 



 
3 

 

(Sokar et al., 2013). The dosage forms of these can either follow capsule, pellet, or tablet 

configurations amongst which is the ’core-in-cup’ tablet system. A typical core-in-cup tablet 

system consists of three different parts: a core tablet, containing the active ingredient, an 

impermeable outer shell, and a top cover plug layer of a soluble polymer, (Danckwerts and 

Watt, 1998; Nagaraju et al., 2009; Sokar et al., 2013; Srinija and Lakshmi, 2016; ElMeshad et 

al., 2020) (Figure 1.2). 

Nonetheless, the present study proposes to employ the same concept in developing a drug 

delivery system comprising an enterically press-coated esomeprazole magnesium trihydrate 

(ESM) core pill, an insoluble pH-dependant plug barrier, a delayed release (DR) cup 

formulation layer of diclofenac sodium (DS) and paracetamol (PAR), and an Immediate 

release (IR) top layer of PAR. In addition to the discovery and development of non-opioid 

analgesics such as the novel VX-548 (moving into Phase III clinical trials) and benzyloxy-

cyclopentyladenosine (BnOCPA); an expedited approach towards formulation-based 

interventions involves research on combinations of currently available active pharmaceutical 

ingredients (APIs) to tap into unexplored synergistic potentials of non-addicting analgesics 

(Kingwell, 2022; Wall et al., 2022). 

 

Figure 1.2: Core-in-Cup PDDS. Reprinted with permission from (Sokar et al., 2013). 

 

1.2 Rationale Behind the Design and Combination 

High-income countries have suffered strains in their health and financial systems as a result 

of the global crisis, unfortunately, the health systems of developing countries are even less 

prepared should the opioid epidemic occur (Harker et al., 2020).  In order to lessen the 

forecasted burdens, there is a need to ensure a reduction in the number of new cases of 

addiction, whether from intentional or unintentional abuse.  A pharmaceutical approach in 

ensuring this involves encouraging the discovery, development, and re-development of low-

abuse potential, non-addicting analgesic formulations for prescription to opioid-naïve chronic 

patients.  



 
4 

 

Adherence to adjunct gastroprotective agents (GPAs) in NSAID users has been established 

to be suboptimal; in fact, it was discovered in one study that more than one-third of NSAID 

users did not use the prescribed GPAs daily, which resulted in a 16% increase in GIT 

complications for every 10% decrease in adherence (Van Soest et al., 2007). Therefore, this 

study proposes a familiar analgesic combination of PAR and DS, comprising prophylactic ESM 

for potential and convenient use in the long-term symptomatic relief of inflammatory pain in 

chronically ill patients. 

The rationale behind the design was based on inherent drug properties, target release sites, 

desired therapeutic effects, and allowance for drug release manipulation.  Whilst diclofenac 

potassium is formulated for release in the stomach, often as IR tablets, DS due to its resistance 

to dissolution in low pH gastric milieu, is designed for duodenal release (Williams and 

Buvanendran, 2011). Following oral administration, DS uniquely accumulates in synovial 

fluid which may explain why its duration of therapeutic effect is considerably longer than the 

plasma half-life of 1 to 2 hr, the dose range for adults with joint inflammatory pain is 150 – 200 

mg/24hrs in adults (Williams and Buvanendran, 2011). Various pieces of research have 

comprehensively proved the synergism between PAR and DS, including new data on the 

analgesic mechanisms of PAR, confirming its efficacy in multimodal, non-opioid, or opioid-

sparing, therapies for the treatment of both acute and chronic pain (Przybyła, Szychowski and 

Gmiński, 2021; Freo, 2022). 

The top layer constitutes an immediate-release formulation of PAR, 250 mg for an early onset 

of analgesia. The cup layer was formulated for the delayed and retarded release of 100 mg of 

DS and 250 mg of PAR in tandem. Lastly, the core is a press-coated 20 mg ESM pill. Because 

ESM rapidly degrades at low pH, i.e., gastric milieu, a low solubility barrier plug was placed 

between the IR layer and DR layer. A schematic depicting the desired release profile is 

represented in Figure 1.3. 

https://www.sciencedirect.com/topics/medicine-and-dentistry/synovial-fluid
https://www.sciencedirect.com/topics/medicine-and-dentistry/synovial-fluid


 
5 

 

 

Figure 1.3: Schematic of the ideal desired release profiles. 

 

1.3 Aims and Objectives of the Study. 

The aim of this study was to design and develop a non-opioid tripartite controlled-release tablet 

for chronic inflammatory pain. The above aim was attained via the following objectives: 

1. Performing pre-formulation studies to characterise and screen various polymer 

combinations for potential use in the formulation, including developing and validating 

an HPLC method for the simultaneous detection of the APIs. 

2. Designing and formulating a tripartite controlled-release tablet and performing process 

validation tests by analysing the matrices' hardness, uniformity of mass, friability, and 

thickness. 

3. Characterisation of the tablet by performing physicochemical studies to determine 

stability and molecular interactions within the matrix and between the layers. 

4. Elucidation of the physico-mechanical properties of the DDS through matrix hydration, 

erosion, and textural analyses. 

5. Performing in vitro drug release studies to determine the drug release profile of the 

DDS and predict the potential release mechanism of the system. 

6. Performing ex vivo permeability studies on porcine duodenal tissue to determine the 

effect of tableting on the permeability profiles of the active ingredients. 

 



 
6 

 

1.4 Overview of This Dissertation 

Chapter One: This chapter provides an introduction and background of this current study. 

Details on the motivation for undertaking this study, the rationale, aims and objectives for the 

study were presented. 

Chapter Two: This chapter presents a comprehensive literature review on controlled-release 

multi-drug oral systems, with concise insight into the currently employed and novel formulation 

techniques. Included therein is a summary of different 3D printing technologies applied in the 

fabrication of customised solid oral drug delivery systems, such as extrusion-based printing 

further subdivided into fused deposition modelling (FDM) and extrusion at room temperature 

(EXT), amongst others. The chapter ends with an expert opinion on how identified hindrances 

in the full implementation of these novel techniques may be tackled. 

Chapter Three: This chapter outlines all the pre-formulation investigations undertaken on 

potential formulation components. Details on the effects of potential polymers/excipients on 

APIs’ characteristics as determined via DSC, TGA and FTIR analyses are presented. Outlined 

as a part of the chapter are steps taken towards the development and validation of an HPLC 

method for the simultaneous quantitation of the APIs during dissolution and permeability 

analysis. 

Chapter Four: This chapter entails the preliminary design and developmental stage, in which 

working formulations were determined through in vitro dissolution studies carried out on 

various drug-loaded structural components of the tablet matrix. In order to distinctly establish 

working concentrations of the functional polymers for each formulation layer, partial blanks 

were formulated and compressed for investigation. Analyses performed highlight the influence 

of key polymers such as super-disintegrant croscarmellose sodium (CCS), hydroxypropyl 

methylcellulose (HPMC K15M), eudragit L 100-55 (EL 100-55) as well as the efficiency of the 

plug as an added protection from gastric degradation of the core formulation. 

Chapter Five: This chapter focuses on the assemblage of the complete and optimal drug 

delivery system, based on the findings from the previous chapter, including in vitro release 

studies and all in-process validation tests. Included therein is the characterisation of the final 

formulation, i.e., establishment of the DDS’s physico-mechanical properties through matrix 

hydration, erosion, and textural analyses. 

Chapter Six:  This chapter expounds on the methodology applied in evaluating the ex vivo 

permeability characteristics of the drug compounds in combination through porcine duodenal 

tissue. Highlighted in the chapter is the effect of tableting excipients/polymers on available 

methods of permeability analysis. 



 
7 

 

Chapter Seven: Concludes on the present research, presenting recommendations for future 

work. 

 

 

 

 

 

 

 



 
8 
 

CHAPTER 2 

LITERATURE REVIEW ON NOVEL FORMULATION TECHNIQUES FOR CONTROLLED 

RELEASE MULTI-DRUG SYSTEMS 

 

2.1 Introduction  

Because of the prevalence and chronicity of both communicable and non-communicable 

diseases such as hypertension, tuberculosis, and diabetes, patients are often prescribed long-

term regimens comprising multiple medications (Gradman et al., 2013; Weverling et al., 1998; 

Cruz et al., 2018). While there is no set definition of polypharmacy, it is commonly described 

as the concurrent prescribing of at least four or five medicines, for instance, a typical regimen 

for a hypertensive patient with hypercholesterolemia contains Enalapril 10 mg, Carvedilol 10 

mg, Spironolactone 10 mg, Hydrochlorothiazide 25 mg at least once daily, and Simvastatin 

20mg (STG, 2015). Following administration requirements to the letter is a sine qua non for 

effective polypharmacy. Unfortunately, both intentional and non-intentional non-adherence are 

frequent consequences of polypharmacy (Payne and Avery, 2011).  

 

Poor medication adherence has been linked to a deterioration in the prognosis of patients with 

non-communicable diseases, coupled with other negative effects such as increased mortality 

and costs (Diseases et al., 2021). Recent findings from a study examining the factors 

associated with non-adherence among older patients with multimorbidity and polypharmacy 

showed a 79.6% prevalence of non-adherence in 74 non-institutionalized patients aged ≥65 



 
9 
 

years with ≥2 chronic conditions (González-Bueno et al., 2021). The former statistics cohere 

with Butler and co-workers’ previous findings, in which non-adherence was associated with 4 

to 11% of all hospitalizations and 7.6% of emergency visits, with a staggering overall incidence 

of 40 to 86% (Butler et al., 2011). A formulation-based solution to the pressing issues of 

polypharmacy was the introduction of fixed dose combinations (FDCs) commonly referred to 

as "polypills” targeted at reducing the risk of mortality and cardiovascular events (Abushouk 

et al., 2022). In 2016, polypills were formally recommended and included in the European 

Guidelines on cardiovascular disease prevention and the World Health Organization proposed 

polypills as a significant strategy for improving cardiovascular disease management (Piepoli 

et al., 2016; WHO, 2016). 

  

As the name suggests these formulations contain multiple active ingredients, each with a 

different pharmacological effect. A commercially available example is PolycapTM constituting 

enteric-coated aspirin, ramipril, simvastatin, atenolol, and hydrochlorothiazide, other examples 

include RamitorvaTM (aspirin, ramipril, and atorvastatin), and StarpillTM (aspirin, losartan, 

atenolol, and atorvastatin) (Yusuf et al., 2009; Webster, Castellano and Onuma, 2017). The 

development of the majority of polypills was motivated by the serious burden and incidence of 

cardiovascular disorders, however, the concerns around polypharmacy are not limited to 

cardiovascular diseases. Furthermore, the rationale behind multi-drug systems hinges on the 

effectiveness of combined therapy, simplified treatment regimens, reduced production and 

storage costs, and efficient supply chain and logistics, in addition to the highlighted grounds 

of enhanced adherence and compliance (Webster, Castellano and Onuma, 2017). However, 

polypills like any other intervention have their drawbacks, notably the production process, 

which has proven to be quite complex. Different procedures are utilized in the classic 

compression process, such as granulation of all active components, individual granulation of 

actives, and drug separation by layering in circumstances where there are incompatibles and 

interactions between the actives (Webster, Castellano and Onuma, 2017).  

More importantly, the mass production of the polypill has been criticised for its one-size-fits-

all approach, which disregards individual patient needs that is, some patients may require 

higher or lower dosages of particular active moieties within the formulation, while others may 

not require all of the drugs contained within the formulation (Abushouk et al., 2022). Moreover, 

bioavailability profiles and dosing requirements of paediatric, adult, and geriatric populations 

vary. Although traditional techniques may be used to customise a pill for a patient, the methods 

are neither cost-effective nor practicable for continuous fast on-demand production (Webster, 

Castellano and Onuma, 2017). This calls for more innovative and flexible production 

techniques that will allow the smooth fabrication of bespoke drug combinations. One such 



 
10 

 

technology is 3-dimensional (3D) Printing, an innovation posing significant promise for patient 

patient-centred therapy (Jamróz et al., 2018). The combination of these two ideas (3D printing 

and multi-drug Systems) represents another step forward in the revolutionisation of 

healthcare. This review will investigate the promising paradigm shift from one medication for 

all to personalised patient-centred medicines, providing an overview of the current state of 3D 

printing techniques for multi-active dosage forms, polymers, and excipients used and their 

effects, the market view, limitations, and potential barriers to full implementation. 

2.2 Summary on 3D Printing Technologies 

3D printing has been described by terms such as layered manufacturing, additive 

manufacturing, computer automated manufacturing, fast prototyping, solid freeform 

technology (SFF), and even artistic science from its inception in the early 1970s 

(Abdulhameed et al., 2019; El-bassyouni, 2020). It has a plethora of applications in 

engineering, dentistry, building, aeronautics, bone regeneration, as well as pharmacy 

(Choonara et al., 2016). To produce a solid entity, the printing process involves layer-by-layer 

deposition of ‘ink' material based on a pre-designed 3D digital model. Although it has been 

around for some time, its use in the pharmaceutical sector is still in its nascent stages, and its 

full potential has yet to be realized (Jamróz et al., 2018; Zhu et al., 2020). A lot of research 

has been done on 3D printing in the medical sector, with a vast amount of literature for 

reference on topics such as the selection of appropriate excipients, printable actives, 

strategies to achieve different drug-release profiles, and the advantages of various 

methodologies (Goyanes et al., 2015; Awad et al., 2018; Horst, 2018). 

 

Operations of the different types of 3D printing technologies have been extensively explained 

in several publications with provisions for the different ways of classifying them (Goyanes et 

al., 2015; Horst, 2018; Abdulhameed et al., 2019; Zhu et al., 2020). A simple classification 

system by Jamroz et al. included powder solidification, liquid solidification, and extrusion. 

Extrusion-based printing is frequently utilized in the production of solid oral dosage forms. The 

approach is further subdivided into fused deposition modelling (FDM) and extrusion at room 

temperature (EXT), the latter of which is confined to thermolabile drugs (Jamróz et al., 2018). 

In liquid solidification, the object is built by either droplet solidification (Drop on Drop deposition 

or Ink Jetting) or solidification of photosensitive liquid (Stereolithography/SLA), whereas in 

powder solidification, the object is built by either solidification of powdered material by high 

energy beam (Selective laser sintering/ SLS) or liquid binding of powdered material (Drop on 

solid deposition or Binder Ink Jetting (BIJ) (Jamróz et al., 2018). Modifications were made to 

SLA to allow for faster, better resolution, and more efficient processing via the incorporation 

of a digital micro-mirror device (DMD) in the optical path of the laser. Whilst SLA printers, 



 
11 

 

require vast amounts of resin for printing, digital light processing (DLP) printers allow for 

customized resin reservoirs and lesser amounts of resin.  Promising applications of DLP 3DP 

include printing medical devices, microneedle-mediated drug delivery systems (Lim, Ng and 

Kang, 2017; Bloomquist et al., 2018), and more recently solid oral dosage forms, illustrated in 

Figure 2.1 below (Kadry et al., 2019). 

 

Figure 2.1: Schematic diagram of the Digital Micromirror Device (DMD) stereolithography 
(DLP 3DP) setup including designs and images of 3D printed theophylline tablets. Reproduced 
with permission from (Kadry et al., 2019) © 2019 Elsevier B.V. Ltd. 

 

The advantages of 3D printing in medication formulation far outweigh the negatives. It enables 

the compartmentalization of drug components, which is especially essential in multi-drug 

systems where interactions and incompatibilities between medicines and excipients are 

possible. Furthermore, unlike traditional techniques, 3D printing is more versatile, allowing for 

adjustments in shape and size to meet the specific demands of a patient (Alhnan et al., 2016). 

From bi-layered tablets to 6-layer tablets, researchers have proved the versatility of 3D printing 

(Gioumouxouzis et al., 2018; Robles-martinez et al., 2019). Although 3D printing has many 

advantages, some of the few minor drawbacks include the final product's look with perceptible 

exterior flaws, and post-processing of the product, particularly in powder-based and extrusion-

based 3D printing (Alhnan et al., 2016).  

2.3 Customisation in Different Population Groups 

2.3.1 Visually Impaired Patients 

For visually impaired patients, receiving medications may present challenges like trouble 

reading labels and differentiating drugs, especially if the once annotated packaging has been 

damaged or lost (Andreadis et al., 2022). 3D printing opens up the possibility of printing Braille 

characters directly onto the pills. Successful attempts were made in printing orally 

disintegrating tablets and Intraoral films with embedded Braille and Moon characters. Visually 



 
12 

 

impaired volunteers who took part in the haptic in vivo evaluation studies confirmed the 

readability of the embedded text and the potential for personalized treatment with 3D printing 

(Eleftheriadis and Fatouros, 2021).    

                                                                               

2.3.2 Paediatric Patients 

The pharmacotherapy of children requires very specific guidelines in regard to dosing and 

special attention to safety and efficacy. A child's sensitivity to bitter ingredients makes easy 

administration and taste key factors to consider in dosage form design for this group 

(Andreadis et al., 2022). Personalized paediatric formulations can be prepared using 3D 

printing, however, ingredients used in 3D printed dosage forms intended for administration to 

children need to be extensively studied for their possible toxicity. Researchers have attempted 

nonetheless to develop delivery systems that appeal to the population, such as chewable 

gelatine-based gummies in the form of Lego™ bricks, including capsules and orodispersible 

miniprintlets, and cartoon-based ibuprofen and paracetamol-loaded chocolate chewable 

tablets (Rycerz et al., 2019; Karavasili et al., 2020; Eduardo, Ana and José, 2021). 

 

2.3.3 Geriatric Patients 

Multimorbidity is a more common occurrence in older patients making them the most 

susceptible to the deleterious effects of polypharmacy. It is this population group that will 

benefit the most from 3D printed multidrug systems, customised to each one’s therapeutics 

needs (Andreadis et al., 2022). Figure 2.2 illustrates the concept of customised therapy 

achieved by 3D printing versus mass-produced conventional systems. 

 

Figure 2.2: Comparison between mass-produced conventional dosage forms-based therapy 
and 3D printing-based personalized therapy. Adapted with permission from (El-Bassyouni, 
2020) © 2020 Elsevier.  

 



 
13 

 

2.4 3D Printed Multi-Drug Dosage Forms 

Spitram® (levetiracetam), a single-active formulation for the treatment of seizures, is the only 

3D printed formulation with Food and Drug Administration (FDA) clearance to date (Kassem, 

Sarkar and Nguyen, 2022). The development of 3D printed multi-system models is presently 

based on proof-of-concept approaches. Oral dosage forms such as captopril, nifedipine, and 

glipizide, fixed-dose combinations efavirenz (EFV), tenofovir disoproxil fumarate (TDF), and 

emtricitabine), and a 6-layered pill containing paracetamol, caffeine, naproxen, 

chloramphenicol, prednisolone, and aspirin make up the majority of these formulations. These 

formulations were printed using a variety of 3D printing methods (Khaled et al., 2015b; Robles-

martinez et al., 2019; Siyawamwaya et al., 2019a). Multidrug systems are not only limited to 

oral dosage forms, but the technology has also found application in drug-eluting implants 

(Domsta and Seidlitz, 2021). Among the numerous approaches available, nozzle-based 

printing, particularly fused deposition modelling, has been the most popular among 

researchers (Kassem, Sarkar and Nguyen, 2022).  

 

2.4.1 3D Printed Oral Multi-Drug Formulations 

2.4.1.1 Formulations Printed by Fused Deposition Modelling  

One noteworthy advantage of FDM in multi-drug formulation development is that it allows for 

multi-material printing, which allows for the extrusion of more than one drug-loaded filament 

in a single printing process (Long et al., 2017). Hot melt-extrusion (HME) is a stand-alone 

process used to manufacture API and polymer filaments (feedstock) prior to FDM printing. 

The method uses heat and pressure to melt and extrude the mixture via an orifice (Repka et 

al., 2018; Lubrizol, 2019). The extruded mixture is aligned with a 3D printer in HME-based 

printing to create the item based on the pre-designed digital model (Zhang et al., 2017). HME 

has proved useful in the creation of solid dispersions, alleviating problems associated with 

poorly soluble APIs and therefore improving dissolution rates and bioavailability (Repka et al., 

2018). The drug loading method in filament production determines the amount of drug that 

can be loaded which in turn influences the rate of drug release from the eventual 3D printed 

solid dosage form. Drug loading by impregnation is limited to a low of about 2% w/w and yields 

rapid drug release, of which both scenarios may not be ideal for multi-drug systems requiring 

sustained release mechanisms. By employing HME in drug-filament production, both higher 

drug loading and prolonged release profiles can be achieved (Karavasili et al., 2020). This 

was demonstrated by Thanawuth et al., (2021), in a study where drug release studies were 

carried out on three, 3D printed tablet formulations, two low-dose formulations, one made from 

impregnation (IMP)-produced drug-loaded filaments and the other from HME-produced drug-

loaded filaments, the third was also HME-produced but with a higher loading (30 % w/w), PLL 



 
14 

 

(PVA) was the choice of polymer in all formulations. The results confirmed that drug loading 

determined by the technique directly influences drug release, both the IMP and HME-produced 

filaments with low drug loading yielded faster release profiles compared to the high drug 

loaded-HME-produced-tablets, in which release was extended to 24 hours with a swelling-

erosion mechanism (Thanawuth et al., 2021). 

 

With growing interest in additive manufacturing of personalised medication with complex 

geometries, integrating and synchronizing FMD and HME using process analytical technology 

(PAT) tools could potentially lead to continuous, larger-scale production of efficient and cost-

effective multi-drug delivery (Long et al., 2017; Wesholowski et al., 2019). Raman 

Spectrometer, Laser-Based Diameter Measuring Module, Acoustic Emission Sensor, High-

speed camera, and Rheometer are some possible PAT instruments that may be included into 

the HME-FDM process and are favourable to multi-drug systems. APIs can be quantified, 

deterioration identified in-line, dosing accuracy increased, viscosity measurement avoiding 

nozzle clogging, no pauses in the printing process, and texture analysis guaranteeing smooth 

feeding of filaments into 3D printers (Hagrasy et al., 2013; Korte and Quodbach, 2018; Yang 

et al., 2018; Andrews et al., 2019; Ponsar, Wiedey and Quodbach, 2020). Figure 2.3 and 2.3 

b illustrate printing processes with and without the inclusion of PAT. 

 

Because various medicines have varying release kinetics and absorption locations, it is critical 

to consider aspects that will affect transit durations through particular areas of the 

gastrointestinal tract when developing controlled-release multiple-drug delivery systems 

(Aulton and Taylor, 2013). For example, metformin and glimepiride, two medicines used to 

treat Type 2 diabetes, (administered as a fixed dose combination or as separate medications) 

have different absorption sites, metformin is mostly absorbed in the small intestine, whereas 

Glimepiride is absorbed in the stomach (Hwang et al., 2013; STG, 2015). Based on these 

criteria, to ensure optimum pharmacotherapy, researchers employed HME/FDM 3D printing 

to fabricate a bi-layered, controlled-release solid dosage form of metformin and glimepiride 

(Gioumouxouzis et al., 2018). Similarly, Windolf and co-workers recently fabricated mini 

floating polypills for Parkinson’s Disease combining Levodopa, benserazide, and pramipexole 

in various dosing for personalized therapy (Windolf et al., 2022). 

 

A new Melt Extrusion Deposition (MED™) 3D printing technology has been created to improve 

the use of FDM by addressing drawbacks such as the requirement for pre-fabrication of 

printable drug-loaded filament and printing precision. The MED™ method combines powdered 

active components and excipient ingredients as starting materials, eliminating the need for 



 
15 

 

prior filament production. Reproducible, accurate, and larger-scale production can be 

performed using high-throughput printer nozzle arrays, handling numerous materials, and 

precise deposition control. This new technology, combined with compartmental model 

designs, allows for the fabrication of bespoke multi-drug systems with modulated release 

kinetics from each compartment (Zheng et al., 2021).  

 

 

Figure 2.3: a. HME coupled FDM 3D printing procedure without in-line PAT tools b. HME 
coupled FDM 3D printing with PAT tools. 

 

 



 
16 

 

2.4.1.2 Formulations Printed by Pressure Assisted Microsyringe Extrusion 

Thermal deterioration is an unavoidable drawback of HME-FMD printing, limiting the number 

of medicines and materials that may be produced using the technology, also known as 

Pressure Assisted Microsyringe (PAM), extrusion at room temperature does not require high 

temperatures. Rather the process involves the preparation of a semisolid gel or paste 

consisting of drug/s and additives. The mass is then continuously extruded layer by layer 

through a syringe-based tool-head. Thus, by employing multi-syringe systems, this technique 

can yield multi-active solid dosage forms with varying kinetics, Figure 2.4 a (Jamróz et al., 

2018; Azad et al., 2020). Khaled and colleagues (2015) used room-temperature extrusion to 

create a multi-compartment, multi-drug system consisting of nifedipine, captopril, and 

glipizide. The formulation was designed to solve issues found in the treatment of hypertension 

and type 2 diabetes, such as dosage dumping, burst phenomena, short elimination half-life, 

and short duration of action (Khaled et al., 2015b). Captopril was released through controlled 

osmosis by incorporating an osmogen sodium chloride into the core of the captopril 

compartment, whereas the other two actives were released via diffusion processes, as shown 

in Figure 2.4b.  

 

Controlled porosity osmotic pump tablets use osmotic pressure principles for controlled 

release, overcoming the impact of the gastrointestinal tract's physiological condition (Shahi et 

al., 2012; Sahoo et al., 2015). This approach is not only simple to use, but it is also appealing 

to patients since it decreases dose frequency while providing the benefit of a longer duration 

of action. Zero-order release, independent of physiological parameters such as pH can be 

achieved. The manufacture of a controlled porosity osmotic pump (CPOP) involves the 

encapsulation of an osmogen core with a semipermeable membrane, which rapidly dissolves 

when in contact with an aqueous medium creating a micro-porous membrane (Sahoo et al., 

2015). Another recent study used extrusion-based printing at room temperature to obtain a 

higher bioavailability of efavirenz (EFV), tenofovir disoproxil fumarate (TDF), and emtricitabine 

(FTC) compared to a non-3D printed commercial version of the same medicines, Atripla® for 

improved HIV therapy (Siyawamwaya et al., 2019b). Nonetheless, extrusion-based printed 

DDS have unappealing characteristics such as low resolution (depending on nozzle size) and 

poor mechanical qualities, necessitating the use of more precise methods such as SLA 

(Domsta and Seidlitz, 2021). 

 

 

 

 



 
17 

 

2.4.1.3 Formulations Printed by Stereolithography  

Stereolithography (SLA) is the original 3D printing method, having been used in 

pharmaceutical technology for the first time in 1984 (Jamróz et al., 2018). It is a laser-based 

technology that uses photo-polymerisation to create a solid three-dimensional object from a 

photocurable viscous liquid enclosed in a vat. A layer is generated by a laser beam following 

a g-coded pattern, then the platform is lowered into the vat for the second layer, and so on 

until the item is finished (Melchels, Feijen and Grijpma, 2010; Abaci et al., 2021). Its 

advantages over nozzle-based methods include greater dimensional precision, a finer finish, 

and a lack of dependency on heat for manufacturing. More significantly, unlike SLA, FDM is 

restricted to a small number of spatially separated medicines in a formulation (Pereira et al., 

2019; Robles-martinez et al., 2019). As a result, Martinez and colleagues used SLA 3D 

printing for the first time to create a multi-layered tablet containing six drugs: paracetamol, 

caffeine, naproxen, chloramphenicol, prednisolone, and aspirin (Robles-martinez et al., 2019). 

However, considerations such as the possibility of API deterioration owing to laser projection 

onto the drug-loaded solution and the requirement for extra API in the manufacture of the 

photocurable resin, restrain its complete usage in production (Abaci et al., 2021).  Recently, 

SLA was employed in the development of multifunctional nanocomposite pills, in which both 

nanoparticles and conventional solid dosage form designs make up a drug delivery system. 

The procedure entails the creation of vat photo-polymerised monoliths that serve as reservoirs 

for drug-loaded nano-carriers. Similarly, researchers may be able to develop more novel 

nanocomposites for multi-modal and multi-compartment drug delivery systems suitable for 

multiple drug systems using SLA-assisted 3D printing (Sharma et al., 2022). 

 

2.4.1.4 Formulations Printed by Selective Laser Sintering  

Selective laser sintering (SLS) is yet another type of laser-based printing that has had limited 

application in 3D printed oral multi-drug systems. This is most likely due to the laser beam’s 

high-energy input, which raises concerns about the likelihood of API and pharmaceutical 

excipient deterioration (Alhnan et al., 2016). Unlike similar powder bed-based techniques, the 

process is faster, and does not require a binder solution; instead, the powdered printing 

material is exposed to radiation, which will either partially or fully melt it for layered fabrication. 

In SLS-printed oral dosage forms, two drug loading approaches can be used: prior to sintering 

and after sintering. The former entails preparing an API and excipient/s powder mixture, which 

is then added to the powder bed for laser-based fabrication of the drug-loaded tablets (Abaci 

et al., 2021). Drug loading after printing is considered a safer approach because the API is not 

exposed to laser radiation. In this approach, a non-drug loaded excipient-based delivery 

system is printed and the API is loaded using coating procedures or infilling techniques. SLS 



 
18 

 

was used for the dual printing of miniprintlets with two rate-controlling systems incorporating 

two model drugs, paracetamol and ibuprofen, whereby one drug was released immediately 

from a kollicoat instant release matrix, whilst the release of the second drug was sustained 

over an extended period using ethyl cellulose (Awad et al., 2019). Great potential exists in the 

use of SLS in oral dosage forms, particularly multi-drug permutations with distinct and uniform 

dosing, permitting discrete separation of the APIs and resolving problems of incompatibility 

and physical interaction, which are major drawbacks in most multi-drug formulations. Table 

2.1 provides examples for each of the afore-explained techniques. 

 

Table 2.1: Summary of 3D Printed multi-drug oral dosage forms. 

Drug Combination 3DP 

Technique 

applied 

Shape and design. Reference  

Nifedipine, 

Captopril and 

Glipizide. 

Extrusion at 

room 

temperature. 

 

Cylinder. 

Compartmentalised: 

Top compartment, Nifedipine and 

Glipizide, release by diffusion. 

The bottom compartment, Captopril, 

release by osmosis. 

(Khaled et al., 

2015b) 

Efavirenz, 

Tenofovir Disoproxil 

fumarate and 

Emtricitabine. 

Extrusion at 

room 

temperature. 

 

Prism 

Separate layers of Efavirenz, Tenofovir 

and Emtricitabine. 

 

(Siyawamwaya 

et al., 2019b) 

Paracetamol, 

Caffeine, 

Naproxen, 

Chloramphenicol, 

Prednisolone and 

Aspirin. 

SLA Cylinder and ring shape 

6 distinct layers of each drug, with 

different release profiles. 

(Robles-

martinez et al., 

2019) 

Lisinopril dihydrate, 

Indapamide, 

Rosuvastatin 

calcium and 

Amlodipine 

besylate. 

Fused 

deposition 

modelling 

(FDM) 

Cylindrical. 

Layered design, each layer constituting 

a different drug. 

(Pereira et al., 

2019) 

Aspirin, 

Hydrochlorothiazide 

Pravastatin, 

Atenolol, and 

Ramipril. 

Extrusion-

based printing. 

 

Cylindrical. 

Aspirin and Hydrochlorothiazide 

immediate release compartment and 

Atenolol, Pravastatin, and Ramipril 

sustained release compartments. 

(Khaled et al., 

2015a) 

Metformin and 

Glimepiride 

HME-based 

Fused 

Deposition 

Modelling. 

 

Bilayer oral solid dosage form 

combining metformin for prolonged and 

glimepiride for immediate drug delivery. 

(Gioumouxouzis 

et al., 2018) 



 
19 

 

 

          

 

Figure 2.4: Selected images of 3D printed multi-drug system configurations. Reproduced with 

permission from a) (Khaled et al., 2015c) 2015 Elsevier; b) (Khaled et al., 2015a) © 2015 

Elsevier. 

Levodopa (LD) 

Benserazide (BZ) 

and Pramipexole 

(PDM). 

HME-based 

Fused 

Deposition 

Modelling. 

Cylindrical. 

PDM and polyvinyl alcohol for rapid 

drug release and a fixed combination 

of LD/BZ (4:1) in an ethylene-vinyl 

acetate copolymer matrix for prolonged 

drug release. 

(Windolf et al., 

2022) 

Isoniazid and 

Rifampicin 

HME-based 

Fused 

Deposition 

Modelling 

Compartmentalised shells. 

Each compartment physically sealed 

for effective retardation of in vitro API 

release 

(Genina et al., 

2017) 

Paracetamol and 

Ibuprofen. 

SLS Spherical Miniprintlets. 

Two distinct regions; Immediate 

release and Sustained release. 

(Awad et al., 

2019) 

Irbesartan, atenolol, 

hydrochlorothiazide 

and amlodipine 

SLA Cylindrical, 2 types of layered designs,  

Type 1 Irbesartan and Atenolol on the 

outer layers and, hydrochlorothiazide 

and amlodipine in the inner layers.  

Type 2 Amplodipine and 

hydrochlorothiazide on the outer layers 

and irbesartan and atenolol in the inner 

layers. 

(Xu et al., 2020) 

a) 

b) 



 
20 

 

2.4.2 3D Printed Multi-Drug Eluting Implants 

The term “drug-eluting implants” refers to drug delivery systems and devices that 

consist of drugs released in surrounding tissue areas after implantation or insertion as a 

means of achieving targeted therapy (Domsta and Seidlitz, 2021). There are various forms of 

implants depending on the area of application. Types such as catheters and screws were 

considered in this study. The most prevalent application of multidrug implants is in bone-

related conditions (Gbureck et al., 2007; Wu, Zheng, Guo and Huang, 2009; Wu, Zheng, Guo 

and Sun, 2009; Vorndran et al., 2010; Inzana et al., 2015; Li et al., 2015; Zhu et al., 2015; Wu 

et al., 2016; Trombetta et al., 2019; Chou et al., 2021). Unlike in oral systems, the commonly 

employed printing technique for implants is binder ink jetting, the advantages of which (over 

the other techniques) include low costs, fast production, multi-material printing, no need for 

supporting structures, low-temperature processing and high porosity products (Domsta and 

Seidlitz, 2021).  

 

Drug loading in 3D printed implants is done either pre-, during or post-printing. Incorporation 

of the drug pre-printing is normally applied in FDM/HME, whereby API and polymer filaments 

are made in an extruder. Binder inkjet printing enables the incorporation of drugs into the 

implant during the printing process as they can be added to the binder solution (Wu, Zheng, 

Guo and Huang, 2009; Inzana et al., 2015; Wu et al., 2016; Trombetta et al., 2019). The drugs 

that are incorporated into the implant matrix before or during the printing process have to 

withstand all conditions of the preparations and the actual printing process. Consequently, 

some sensitive drugs are excluded from those mechanisms due to their degradation 

properties. Post-printing loading on or into the 3D printed implant can either be done by, 

coating (Boyer, Ballard, et al., 2018; Boyer, Woerner, et al., 2018; Poudel et al., 2020), 

immersion into the drug solution under a vacuum to aid absorption, incubation with sublimated 

iodine (Boyer, Woerner, et al., 2018), use of supercritical carbon dioxide (Ngo et al., 2020) or 

manual filling of the processed drug into the 3D printed hollow or reservoir device (Arany et 

al., 2020; Stewart, Domínguez-Robles, McIlorum, Gonzalez, et al., 2020; Stewart, 

Domínguez-Robles, McIlorum, Mancuso, et al., 2020). These mechanisms can be quite 

cumbersome and are limited to porous implants. Table 2.2 provides a summary of developed 

3D printed multi-drug implants.  

 

 

 

 

 



 
21 

 

Table 2.2: 3D Printed multi-drug implants. 

Implant 
type 

Drugs loaded 3DP 
Technique 

Design and Objective Reference  

Stents 
and 
Catheters. 

Gentamicin 
Sulphate, 
Methotrexate 

HME/FDM Disc, bead, catheter. 
3D printing of different constructs 
with antibiotic or 
chemotherapeutic-eluting 
filament. 

(Weisman 

et al., 
2019) 

Bone 
treatment 
screws 

Vancomycin 
Hydrochloride, 
Ofloxacin, 
Tetracycline 
Hydrochloride 

Binder Ink 
jetting 

Cylinder 
Drug adsorption and desorption of 
low-temperature 3D printed 
ceramic scaffolds. 

(Gbureck 

et al., 
2007) 
 

Levofloxacin, 
Rifampicin 
Isoniazid, 

Binder Ink 
jetting 

Multi-layered cylinder. 
For the bi-modal release profile. 

(Wu, 
Zheng, 
Guo and 
Huang, 
2009) 

Isoniazid  
Rifampicin 

Binder Ink 
Jetting 

Programmed sequentially release 
of multidrug implant. 

(Wu, 
Zheng, 
Guo and 
Sun, 2009) 

Levofloxacin, 
Tobramycin 

Binder Ink 
Jetting 

For bone tuberculosis treatment 
for treatment of chronic 
osteomyelitis. 

(Wu et al., 
2016) 
 

Vancomycin, 
Heparin, 
rhBMP-2 

Binder Ink 
Jetting 

Scaffold 
Bio-ceramic implants with high 
accuracy of drug deposition to 
modify the release. 

(Vorndran 

et al., 
2010) 

Isoniazid,  
Rifampicin 

Extrusion Scaffold. 
3D printed scaffolds with 
antitubercular drugs in animal 
model 

(Li et al., 
2015; Zhu 

et al., 
2015) 

 Rifampicin, 
Vancomycin 

Binder Ink 
Jetting 

Scaffold. 
Simultaneous local delivery of 
Rifampicin and Vancomycin from 
3D printed ceramic scaffolds for 
bone infection treatment 
examined in a mouse model. 

(Inzana et 
al., 2015) 

 Rifampicin, 
Sitafloxacin 

Binder Ink 
Jetting 

Scaffold. 
3D printing of antibacterial 
scaffolds for osteomyelitis 
treatment. 

(Trombetta 

et al., 
2019) 

 Vancomycin, 
Ceftazidime 

Extrusion Screw. 
Influence of Printing parameter on 
drug-eluting screws 3D printed by 
a solution-technique 

(Chou et 
al., 2021) 

 

2.5 Additive Materials Used in 3D Printing of Multi-Drug Systems 

One of the major constraints preventing mass adoption of 3D printing for biomedical 

manufacturing is a lack of 3D printing biomaterials that is, polymers, biomaterials, hydrogels, 

and bioinks that are functional for 3D printing, biocompatible, and perform well from a 

biomechanical standpoint (Pugliese et al., 2021). Of the aforementioned 3D printing materials, 



 
22 

 

polymers are the most commonly employed biomaterial in multi-drug systems (Khaled et al., 

2015b, 2015a; Awad et al., 2019; Robles-martinez et al., 2019; Siyawamwaya et al., 2019b). 

The ability to modulate the release of different actives in multi-drug systems forms the basis 

upon which polymers are selected in the 3D printing thereof. Other equally important 

characteristics include the materials’ printability, ease of processability, cost, biocompatibility, 

and degradation rates. In fused deposition modelling (FDM) techniques polymers are 

processed into drug-loaded filaments prior to printing, SLS in the form of powder beads, 

solutions in SLA, and gels in direct ink writing (DIW). Polymers are incorporated as either 

binders, disintegrants, compression aids, diluents, or fillers for modulation of drug release.  

Because of their application versatility, polymers are employed in pharmaceutical 3D printing 

for a variety of purposes, such as controlling dosage shape, size, and drug release. More 

importantly, the majority of them are biocompatible, biodegradable, have manipulable 

mechanical properties, and degradation rates, and can be dissolved in rapidly evaporating 

organic solvents such as dichloromethane (Pugliese et al., 2021). 

 

The type of polymer or material employed in 3D printing depends on the technique being 

applied although some polymers may be used in more than one technique. Generally, in 

FDM/HME printing thermoplastic polymers such as polycarbonate, acrylonitrile butadiene 

styrene (ABS), polylactic acid (PLA) and nylon are used; SLS uses Poly ε-caprolactone (PCL) 

and polyamides, in inkjet printing any polymer that can be supplied as powder may be used 

(Jain et al., 2018) whilst in SLA, liquid photosensitive polymers such as epoxy or an acrylate 

based resin e.g polyethylene glycol diacrylate and photoinitiators such as diphenyl (2,4,6-

trimethylbenzoyl)-phosphine oxide (DPPO) are employed (Healy et al., 2019). Numerous 

polymers of natural and synthetic origin have found applications in biomedical 3D printing. For 

instance, natural polymers like gelatine, collagen, alginate, and chitosan are usually utilized, 

but they frequently necessitate cross-linkers which could be cytotoxic, thus synthetic polymers 

have recently gained attention for 3D printing to avoid such manner of drawbacks (Gross et 

al., 2014; Stansbury and Idacavage, 2016; Ligon et al., 2017).  

 

Cellulose-based polymers have long been used in the pharmaceutical industry to produce 

solid dosage forms, and they have shown great promise in 3D printing techniques. Of the two 

main cellulose derivatives, cellulose ethers comprise of the commonly employed 

methylcellulose, ethyl cellulose (EC), hydroxypropyl cellulose (HPC). The derivatives of which 

are formed by substitutions with methyl and hydroxypropyl groups yielding the likes of 

hydroxypropyl methylcellulose (HPMC), a widely studied polymer. Drug release from HPMC 

matrices is retarded using higher molecular weight and viscosity grades. As the degree of 



 
23 

 

substitutions increases, the solubility profiles shift from dilute alkali to water and finally to an 

organic-solvent-soluble stage (Raj et al., 2021).  

 

A promising approach in controlled release systems, is the quarternisation of polymers, that 

is, the addition of an amino group, for example, PQ-10 also known as quaternized 

hydroxyethylcellulose ethoxylate, a cationic cellulose derivative. The unique ability of these 

polyelectrolyte complexes (PEC) to self-assemble has sparked interest in 3D printing 

applications, including multidrug systems (Siyawamwaya et al., 2017). In a recent study by 

Siyawamwaya and colleagues, a novel PEC of electrostatically bonded PQ-10 and humic acid 

was synthesised and used as bio-ink in 3D printing an antiretroviral multi-drug system for 

enhanced bioavailability, as shown in Figure 2.5.  

 

Figure 2.5: Picture of the self-assembly of HA and PQ-10 and the fibrous PECs collected by 
filtration before drying. SEM image of 3D printed FDC, alongside prolonged drug release 
profiles of a) Efavirenz (EFV), b) Tenofovir Disoproxil Fumarate (TDF) and c) Emtricitabine 
(FTC) in comparison to the commercial version, Atripla®. Reproduced with permission from 
(Siyawamwaya et al., 2019a) 2019 Elsevier. 

 

PCL and PLA are low-cost, biodegradable, non-toxic, hydrophobic polyesters, which can be 

used alone or in combination. PCL has a melting point of 55–60 °C, Tg of −54 °C, is soluble 

in organic solvents and is commonly used for long-term implant delivery devices due to its 

very low in vivo degradation and can be used in tablets and nanotubes (Langer, Basu and 

Domb, 2016). Several forms of PLA exist because of the chirality of the starting monomers, 

i.e., lactic acid (L) and lactide (D). These L or D configurations own various properties and 



 
24 

 

have the ability to form stereo-complexes between the L-PLA and D-PLA forms giving rise to; 

PDLA PLGA poly (lactic-co-glycolic acid), PLLA (poly-l-lactic acid) and PDLLA (poly-d,l-lactic 

acid ) (Ligon et al., 2017; Azad et al., 2020). The latter two possess favourable thermal and 

mechanical properties, a Tg range of 55–65 °C and mechanical strength of 1.9 to 4.8 GPa. 

Therefore, PCL is often blended with the chiral forms of PLA to achieve better erosion 

properties (Jain et al., 2018). 

 

Eudragit® represents a set of synthetic polymethacrylate, non-biodegradable, non-absorbable, 

nontoxic and amorphous polymers. According to Evonik, all Eudragit polymers have 

thermoplastic properties, low glass transition temperatures (between 9 °C and > 150 °C), high 

thermostability, and high miscibility with APIs and other excipients (Evonik, 2018). Varying the 

functional group on the polymer dictates the type of drug release it is best suited for. For 

example, the Eudragit E series, soluble at low pH is used in immediate-release formulations, 

L and S series show delayed release in drug formulations. Eudragit® RL and Eudgrait® RS are 

insoluble with pH-independent swelling, Eudragit® RL has high permeability while Eudragit® 

RS has low permeability. Thus, combining the series together enables pharmaceuticals with 

customized time-controlled release profiles. As a water-insoluble thermoplastic polymer, EC 

is often used for its sustained release capabilities in FDM 3D printing (Thakral, Thakral and 

Majumdar, 2013; Okwuosa et al., 2017).   

 

Other immediate release polymers include HPMC E5 and PVA a biocompatible, hydrophilic 

thermoplastic polymer, exhibiting a Tg of 85 °C, a melting point range of 180 to 228 °C. PVA 

is suitable for immediate-release tablets as it dissolves more readily in hydrochloric acid (Azad 

et al., 2020). Khaled in the construction of a multidrug compartmentalised system, employed 

croscarmellose sodium (CCS), sodium starch glycolate (SSG) (disintegrants), 

polyvinylpyrrolidone (PVP K30) (a binder) and D-mannitol (a filler), in making the joining layer 

of the two compartments. It was designed to disintegrate quickly within the 1st hour of the 

dissolution test and allow the tablet to split into two parts with different drug release 

mechanisms (Khaled et al., 2015b). PVA may also be used in making individualised gastro-

resistant tablets, by creating a drug-loaded PVA core with an enteric shell. Another study also 

suggests that the total drug release can be achieved within 3 minutes by reducing the infill 

rate of PVP tablets to 50 %, which in turn increases the porosity of tablets (Okwuosa et al., 

2017; Kempin et al., 2018). For the manufacturing of implants, biocompatible and 

biodegradable polymers such as PLA, poly(lactic-co-glycolic acid) (PLGA) or polycaprolactone 

(PCL) are commonly used, others include cellulose derivatives, PVA, Eudragit, ethylene vinyl 

acetate (EVA), polyethylene oxide (PEO) and thermoplastic polyurethane (TPU) (Shaqour et 



 
25 

 

al., 2020). Wu et al (Wu et al., 2016), employed one of the chiral forms of PLA, PDLLA (Mw = 

100 kDa) in the fabrication of a 3D printed multi-drug implant for chronic osteomyelitis. 

 

2.5.1 Other High Functionality Polymers 

The advent of 3D printed biomedicals has stimulated the development of a whole range of 

high-performance polymers such as polyether ether ketone (PEEK), polyether ketone (PEKK), 

Polyetherimide (ULTEM) and engineering ceramics like alumina, zirconia and silica. The 

unique properties of these polymers, that is resistance to extreme heat, incredible hardness, 

biocompatibility, and rubber-like qualities, set them apart. PEEK is the most popular of the 

aforementioned materials. Its popularity is attributed to a variety of favourable properties, 

including heat resistance of up to 260 °C, water resistance, lightweight compared to metals, 

and, most importantly, biocompatibility. All current PEEK materials for 3D printing are 

obtainable as filaments and can be 3D printed using FDM machines (Beamler, 2019). Kang 

et al., successfully employed FDM in the development of PEEK implants for bone mandibular 

defects, producing a novel mandibular reconstruction model with high stability, proven by 

deformation results (Kang et al., 2021). However, PEEK, like other high-functionality 

polymers, has its limitations, including poor integration with surrounding bone tissue post-

implantation. Therefore, to improve PEEK bioactivity, numerous strategies for functionalizing 

the PEEK surface and changing the PEEK structure have been proposed (Gu et al., 2021). 

Composites such as graphene and nanomaterials, and even 4D materials also fall under the 

category of high-performance polymers. 

 

2.6 Limitations and Barriers to Implementation 

Many specialists around the world share the ambition for 3D printing, with new research 

papers being published more frequently than not to highlight the technology's potential in 

formulation development and patient care. Regardless of the hype, countries are certainly 

encountering difficulties in introducing and implementing this technology within the 

pharmaceutical sectors. Aprecia Pharmaceuticals’ Spritam® (Levetiracetam), the first and only 

commercialised 3D printed pharmaceutical to this date confirms this. Large biopharmaceutical 

firms have shown little interest in this field (Wright, 2005). 

 

2.6.1 Regulatory Constraints 

Despite the FDA's (United States of America) efforts as forerunners in implementing 3D 

printing, as evidenced by the Guide provided in 2017 (Reddy et al., 2020), there are still some 

grey areas in terms of regulatory requirements, making it a big hurdle for manufacturers 

worldwide (Bhusnure et al., 2016). Biomedical systems, unlike other 3D printed products, 



 
26 

 

require special attention when it comes to rules and constraints. Compared to the conventional 

ways of developing oral dosage forms, 3D printing processes are distinct and still novel in 

many pharmaceutical manufacturing sectors. As a result, quality control testing on items such 

as tablets needs to be revised. Promisingly, in March 2021, the Medicines and Healthcare 

Products Regulatory Agency (MHRA) proposed a new regulatory framework towards the 

development of point-of-care manufacturing and supply, including 3D printing technologies for 

customised medicine production (Abdul and Trenfield, 2022). 

 

2.6.2 Processing Parameters 

2.6.2.1 Material Attributes and Selection 

The type of binders used varies depending on the product being created. Biocompatible 

binders must be considered in order to develop biomedical products, and knowledge about 

these binders is still restricted. The materials employed must be of good quality and safe for 

use in the body of the patient; the only materials that are compatible are those that are 

organically based, which are unfortunately presently scarce (Shahrubudin et al., 2020). 3D 

printed dosage forms possess low mechanical properties, which may be favourable in the 

case of oral dosage forms designed for immediate release. Nonetheless, the printed product 

should have acceptable tensile, compressional strength and flexible rigidity where applicable. 

The optimum bone tissue scaffold, for example, has macro-pores of 300–900 μm and porosity 

of 60–95 % in load-bearing bone tissue regeneration. Fortunately, with Selective Laser Melting 

(SLM) 3D printing technique, porous titanium implants with great osteo-integration in vivo 

performance with pore size 400–1000 μm can be fabricated (Shahrubudin et al., 2020). 

 

2.6.2.2 Printer Accuracy 

Low dimensional accuracy may seem counterintuitive when discussing 3D printing, yet 

depending on the object being developed, such as implants and body parts, high levels of 

accuracy may be important. When employing randomly selected equipment and materials, 

producing 3D printed biomedical items with the exact size and structure is difficult. Low 

dimensional accuracy products will not fit in the body, lowering clinical success rates. The 

difficulty is to overcome product shrinkage throughout the curing and cooling process. 

 

2.6.2.3 Return on Investment (ROI) 

Additionally, respondents in a survey done in Malaysia highlighted four hurdles to the 

implementation of 3D printing with regard to management: re-education of workers, high-

priced products, a lack of guidelines, and cyber-security issues. Because the technology is 

still a relatively new notion in many circles, basic operational knowledge may be insufficient. 



 
27 

 

Employees will need to enhance their education and skill levels for organ