JOURNAL CLUB PRESENTATION (20L81S0709-PA) Presented by: T.JAYASREE (Department of pharmaceutical analysis ).RIPER, anantapur

1. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 1
Journal club presentation as a part of curricular requirement
for II year M.Pharm I Semester
Presented by
Ms. T. Jayasree (20L81S0709)
Pharmaceutical analysis
Under the guidance/Mentorship of
S. Shakir Basha, M.Pharm
Department of pharmaceutical Analysis
Compatibility and stability studies involving
polymers used in fused deposition modeling 3D
printing of medicines

2. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 2
Title, Authors and Affiliations

3. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 3
• Introduction
• Materials and Methods
• Results and Discussion
• Conclusion
• Reference
Contents

4. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 4
• The analytical tools like derivative thermogravimetric analysis and differential
exploratory calorimetry are advantageous in stimulating accelerated aging during
the assay.
• Enthalpy and mass loss involved in phase transition phenomena and chemical
reactions should be monitered, it is possible to access the sample stability under
virtual processing and storage conditions.
• The thermal analysis combined with spectroscopic and diffractometric
measurements helpful in anticipating conclusions on drug stability in which the
health guidelines of drug stability studies take several months to years.
• In recent studies the fused deposition modelling three-dimensional printing has one
of the most promising techniques to elaborate drug products.
Introduction

5. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 5
• Notably, a 3D-printed dosage form can have its composition, release kinetics,
shape, and size specifically designed to meet patients specific needs.
• The raw materials are initially subjected to pharmaceutical hot-melt extrusion to
form drug loaded filaments.
• The 3D/FDM printers build medicines under electronic control from these
filaments melting.
• The filaments used in 3D/FDM printing are composed of plastic polymers heated
in the print nozzle at temperatures above their glass transition and deposited in
overlapping layers of variable height and dimension on a flat surface with heating
control.
Introduction

6. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 6
• This recent incorporation of this technology in the pharmaceutical field, little is
known about such printed products stability, especially those containing thermo-
sensitive drugs.
• The four promising polymers for pharmaceutical use involving such technology
were selected EUL, PVPVA, PVA, and SOL which were tested by using two model
drugs, paracetamol and metoprolol tartrate.
• The drug-polymer sets were subjected to thermal stress, aged in a stability chamber
and evaluated regarding their morphology, thermal crystallographic and
spectroscopic profiles.
Introduction

7. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 7
Materials
• PCM was purchased by Purifarma (São Paulo, Brazil), and MTL was provided by
Purifarma (Anápolis, Brazil).
• Plasdone® K-29/32 (poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA), was
donated by Ashland Specialty Ingredients (Covington, LA, USA)
• Eudragit® L100 (EUL, methacrylic acid-methyl methacrylate copolymer, was
provided by Evonik (Essen, Germany)
• Soluplus® (SOL, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol
copolymer, was a gift from BASF (Ludwigshafen, Germany)
• Parteck ® MXP (PVA, polyvinyl alcohol) was donated by Merck (Darmstadt,
Germany).
Materials and Methods

8. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 8
Sample preparation
• The polymers with different physical-chemical properties like PH-dependent
solubility of EUL, the rapid aqueous disintegration of PVA, the high hydrophilicity
of SOL and PVPVA.
• Enable the preparation of different drug system by 3D-printing, such as gastro-
resistant, immediate-release and orodispersible dosage forms.
• PCM or MTL and polymer should be in 1:1 (m/m) proportion were prepared and
submitted to a double heating treatment, stimulating the thermal stress.
• The samples were heated twice in an oven for 2 min each, temperature for PVPVA
mixtures (100 and 135 ºC), SOL 84 mixtures (120 and 180 ºC), EUL (120 and
160ºC), and PVA (160 and 180ºC).
Materials and Methods

9. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 9
• The double-heated samples were subjected to an accelerated stability protocol.
• The samples in open container were aged at 40°C and 75% of relative humidity in a
stability chamber for 3 months and analyzed at different times (15, 30, 60 and 90
days) according to the assay.
Thermal analysis
• Thermal analysis tests were performed in the binary mixtures before and after
double heating and accelerated aging at different times, as well as in the
compounds alone subjected to the same treatments.
Materials and Methods

10. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 10
• Samples were evaluated by DSC using approximately 5 mg of the samples placed
in aluminum crucibles.
• The equipment operated under a dynamic N₂ at 10°C/min from 30° to 450°C.
Drug crystallinity = ΔHM / ΔHdrug x 100
• Thermogravimetric determinations were performed using approximately 5 mg of
the samples placed in platinum crucibles.
X-ray powder diffraction (XRPD)
• XRPD spectra for untreated and aged-90d samples.
• This analysis, the diffraction patterns were obtained on angles in the range of 5 to
60°.
Materials and Methods

11. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 11
Fourier transform infrared spectroscopy (FTIR)
• Infrared spectra of binary mixtures and their components were recorded in a
transmittance range from 600 to 4.000 cm-1
• Comparisons among untreated and treated samples were performed, calculate the
correlation coefficient.
Microphotographs
• The morphological aspect of the sample was analysed by optical microscopy using
a stereoscope connected to a video camera.
• The images were plotted and no masks or filters were applied to the original
pictures.
Materials and Methods

12. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 12
Thermal processing of the selected model drugs
• HME and 3D printing processes requires high temperature.
• The speed involved in the HME and 3D printing, which takes only a few minutes
to be performed, in both processes, temperatures above 100°C are required, which
can affect the stability of the dosage form, entailing a non-desirable degradation.
• PCM was chosen as a thermostable drug , according to the DTG analyzes, the
decomposition of this drug occurred in the range of 200-305 ºC .
• The heating used in this study to simulate HME processing and 3D printing was in
the range of 160-180 ºC, which is relatively out of the drug decomposition interval.
• The DSC profile of the PCM did not cause changes in the drug's melting event.
• The correlation coefficients between the spectra of the untreated drug and the
treated samples showed values between 0.90 and 0.93.
Results and Discussion

13. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 13
• The samples heating was enough to stimulate drug melting and subsequent
recrystallization without altering the drug crystalline phase, as demonstrated by the
X-ray diffraction spectra.
• MTL, was chosen as a thermosensitive drug.
• The DTG showed an intense mass loss in the range of 170 to 240 ºC.
• The DSC of the double heated and aged samples show the drug melt at lower
temperatures, reaching a change of 4 ºC in the case of MTL aged-90d, with a
reduction of about 15% in its enthalpy.
• The FTIR spectra of the MTL samples submitted to accelerated aging showed a
high correlation coefficient with the untreated sample (above 0.9), FTIR bands are
recognized in MTL aged-90d.
• The drug crystals have the same original crystalline phase, with a minor oscillation
of the baseline, indicating traces of the amorphous drug in the sample.
Results and Discussion

14. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 14
 Thermal processing and aging of the polymeric matrices with PCM
• The incorporation of PCM into EUL did not change the thermal profile of the drug.
• Both the melting event and the typical decomposition profile of PCM unaffected
even after the accelerated aging of the samples.
• The infrared spectra showing all the bands corresponding to the drug functional
groups, with a high correlation coefficient (above 0.9) of the fresh sample
compared to the treated and / or aged samples.
• The results of XRPD showed the maintenance of the original crystalline phase of
PCM, an increased amorphous component was observed in the PCM-EUL aged-
90d sample.
• A similar effect was recently reported in matrix tablets of acrylic polymers
containing PCM, literature shows that EUL has a high affinity for PCM by
establishing hydrogen bonds with this drug's amide group.
• Optical microscopy images showing the formation of slightly yellow agglomerates.
.
Results and Discussion

15. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 15
• PCM-PVPVA systems, showed substantial thermal changes in the DSC.
• The infrared spectra showed that the bands corresponding to the PCM functional
groups could be identified without modifications, with a great correlation between
the spectra of the untreated mixtures and stressed samples (r>0.95).
• The aging of the PCM-PVPVA under high relative humidity conditions caused a
visible water uptake and agglomerates formation, without causing damage to the
sample chemical stability.
• The PCM was compatible with PVPVA even in extreme temperature conditions.
• DTG showed that while the decomposition profile of PCM is recognized in the
untreated PCM-PVA with at 203 ºC, the sample that underwent double heating
revealed a change in the degradation profile.
• The FTIR spectra of these samples revealed intensity loss of the bands
corresponding to the drug's functional groups.
Results and Discussion

16. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 16
• An oscillations in the X-ray diffractogram baseline.
• In this combination of PCM and PVA, the double heating to simulate extrusion and
3D printing processes to deleterious chemical reactions between the drug and the
polymer, making clear the chemical incompatibility.
• SOL showed a strong affinity for PCM, suggesting the complete solubilization of
the drug in the polymeric matrix after the thermal treatment.
• Minor oscillations, according to the DTG data and also small changes in the PCM
characteristic bands.
• The sample morphology revealed aggregates formation without any color change,
corroborating the chemical stability of this mixture.
Results and Discussion

17. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 17
Thermal processing and aging of the polymeric matrices with MTL
• The system MTL-EUL indicating complete solubilization of the drug in the
polymeric matrix after such thermal processing.
• optical microscopy, the glassy morphology of the sample is observed.
• The correlation coefficients of the untreated sample spectrum and the aged samples
showed values consistently above 0.9.
• In the system containing MTL and PVPVA that underwent double heating, a slight
broadening of the melting peak was observed.
• The XRPD spectra confirm the partial drug solubilization in the polymeric matrix.
Results and Discussion

18. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 18
• The MTL samples mixed with PVA or SOL showed signs of strong drug-polymer
interaction with the almost disappearance of the drug melting event.
• Drug solubilization in the polymeric matrices after the double heating that
simulates the extrusion and 3D printing processes.
• The microscopical appearance of the aged samples was glassy and without color
changes.
• In the mixture containing MTL and SOL, the interaction between the components
changes the decomposition profile, whose temperature range occurs at least 10
degrees later than expected, suggesting a protective effect of the polymer matrix.
• The sample with the longest aging time showed a high correlation with the
untreated mixture in the FTIR spectra, proving the chemical integrity of MTL
Results and Discussion

19. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 19
Authors conclusion
• The author states that, this study, involving two model drugs with different
sensitivity to temperature and four polymeric matrices.
• The thermal stress accumulated in the double thermal processing of the samples
and their forced aging, there are good prospects that these drug products have
adequate stability for commercialization.
• Even in certain circumstances, interactions with polymers act as a protective factor
to the drug.
My conclusion
• I concluded that based on the above results obtained, by establishing protocol that
stimulate processing and storage conditions for pharmaceutical dosage forms using
this new technology.
• The HME and 3D printing process was rapid with reliable results.
conclusion

20. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 20
1. A. Talvani, M.T. Bahia, L.C.L. de Sa-Barreto, et al., Carvedilol: decomposition
kinetics and compatibility with pharmaceutical excipients, J. Therm. Anal.
Calorim. 115 (2014) 2501– 350 2506.
2. R. Ferreira-Nunes, T. Gratieri, G.M. Gelfuso, et al., Mixture design applied in
compatibility studies of catechin and lipid compounds, J. Pharm. Biomed. Anal.
149 (2018) 612–617.
3. B. Rojek, B. Suchacz, M. Wesolowski, Artificial neural networks as a supporting
tool for compatibility study based on thermogravimetric data, Thermochim. Acta
659 (2018) 222–231.
4. F. Fina, A. Goyanes, M. Rowland, et al., 3D printing of tunable zero-order
release printlets, Polymers (Basel) 12 (2020) E1769.
References

21. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 21
5. S. Ayyoubi, J.R. Cerda, R. Fernandez-Garcia, et al., 3D printed spherical mini-
tablets: Geometry versus composition effects in controlling dissolution from
personalised solid dosage 375 forms, Int. J. Pharm. 597 (2021) 120336.
6. V.M. Vaz, L. Kumar, 3D printing as a promising tool in personalized medicine,
AAPS PharmSciTech 22 (2021) 49.
7. M. Cunha-Filho, M.R. Araújo, G.M. Gelfuso, et al., FDM 3D printing of
modified drug delivery systems using hot melt extrusion: a new approach for
individualized therapy, Ther. 380 Deliv. 8 (2017) 957–966.
8. F.Q. Pires, I. Alves-Silva, L.A.G. Pinho, et al., Predictive models of FDM 3D
printing using experimental design based on pharmaceutical requirements for
tablet production, Int. J. 386 Pharm. 588 (2020) 119728
References

22. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 22
9. K. Ilyes, N.K. Kovacs, A. Balogh, et al., The applicability of pharmaceutical
polymeric blends for the fused deposition modelling (FDM) 3D technique:
Material considerations printability-process modulation, with consecutive effects
on in vitro release, stability and degradation, Eur. J. Pharm. Sci. 129 (2019) 110–
123.
10. W. Kempin, V. Domsta, I. Brecht, et al., Development of a dual extrusion
printing technique for an acid- and thermo-labile drug, Eur. J. Pharm. Sci. 123
(2018) 191–198.
11. G. Matijasic, M. Gretic, J. Vincic, et al., Design and 3D printing of multi-
compartmental PVA capsules for drug delivery, J. Drug Deliv. Sci. Technol. 52
(2019) 677–686
12. A.Q. Low, J. Parmentier, Y.M. Khong, et al., Effect of type and ratio of
solubilising polymer on characteristics of hot-melt extruded orodispersible films,
Int. J. Pharm. 455 (2013) 404 138–147.
References

23. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 23
13. L.F.B. Malaquias, H.L. Schulte, J.A. Chaker, et al., Hot melt extrudates
formulated using design space: one simple process for both palatability and
dissolution rate improvement, J. Pharm. Sci. 107 (2018) 286–296.
14. E. Villicana-Molina, E. Pacheco-Contreras, E.A. Aguilar-Reyes, et al., Pectin
and chitosan microsphere preparation via a water/oil emulsion and solvent
evaporation method for drug delivery, Int. J. Polym. Mater. Polym. Biomater. 69
(2020) 467–475.
15. R.M. Borkar, B. Raju, R. Srinivas, et al., Identification and characterization of
stressed degradation products of metoprolol using LC/Q-TOF-ESI-MS/MS and
MSn experiments, Biomed. Chromatogr. 26 (2012) 720–736.
16. Y. Ikeuchi-Takahashi, S. Ito, A. Itokawa, et al., Preparation and evaluation of
orally disintegrating tablets containing taste masked microparticles of
acetaminophen, Pharmazie 75 (2020) 2–6.
References