Authors
- Derar OmariDepartment of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Yarmouk University, Irbid, Jordan. yhttps://orcid.org/0000-0002-1939-8640
- Assayed SallamTQPharma, Amman, Jordanhttps://orcid.org/0000-0002-7872-2084
- Iyad RashidTQPharma, Amman, Jordanhttps://orcid.org/0000-0001-5791-1225
- Shereen M. AssafDepartment of Pharmaceutical Technology, Faulty of Pharmacy, Jordan University of Science and Technology, P. O. Box 3030 Irbid 22110, Jordan.https://orcid.org/0000-0002-3888-9330
- Faisal AkaylehFaculty of Pharmacy and Medical Sciences, University of Petra, Amman 11196, Jordanhttps://orcid.org/0000-0002-7225-0936
- Khaldoun A. Al-Sou′odDepartment of Chemistry, Faculty of Science, Al Al-Bayt University, P. O. Box 130040, Mafraq, 25113, JORDANhttps://orcid.org/0000-0003-1674-9705
DOI:
https://doi.org/10.5599/admet.2569Keywords:
Tablet compressibility, crystallinity, molecular modeling, carbonyl oxygen of modafinilAbstract
Introduction: Modafinil, a wakefulness-promoting agent, is primarily used to treat excessive daytime sleepiness associated with narcolepsy and fatigue. As a BCS class II drug, modafinil exhibits low solubility and high permeability, with its crystalline structure significantly impacting dissolution, bioavailability, and compressibility. This study explores the use of microwave energy to alter the crystalline structure of modafinil in the presence of Gelucire® 48/16, aiming to improve its pharmaceutical properties. Methods: Modafinil was treated with microwave energy to form complexes with Gelucire® 48/16, and the resulting formulations were compared to hot-melt complexes and physical mixtures. The structural and thermal properties of the complexes were characterized using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy. Compressibility and compactibility were evaluated through Kawakita model analysis and response surface methodolog). The effect of microwaves on molecular interactions was further investigated using molecular modeling. Results: XRPD analysis revealed distinct crystalline patterns for microwave and hot-melt complexes compared to physical mixtures, with increased amorphousness observed through crystallinity, relative crystallinity, and relative intensity parameters. DSC thermograms indicated a reduction in melting endotherms and heat flow, suggesting structural changes due to complex formation. Compressibility and compactibility studies demonstrated optimal performance at low Gelucire® content, with microwave-treated complexes exhibiting superior properties to untreated mixtures. Molecular modeling confirmed dipole-dipole interactions between modafinil and the hydrophilic portion of Gelucire®. Conclusions: The study demonstrates that microwave energy effectively alters the crystalline structure of modafinil in the presence of Gelucire® 48/16, enhancing its amorphousness, compressibility, and compactibility. These findings highlight the potential of microwave-assisted complexation as a novel approach to improve the pharmaceutical performance of BCS Class II drugs like modafinil.
Downloads
Download data is not yet available.
References
D. Mutlu, B. Kültürsay, A. Karagöz. Modafinil-induced ventricular arrhythmia: A case report. Türk Kardiyoloji Derneği Arşivi 50 (2022)7 9-82. http://doi.org/10.5543/tkda.2022.21084
S. Aurora, N. Aurora, P. Datta, K. Rewers-Felkins, T. Baker, T.W. Hale. Evaluating transfer of modafinil into human milk during lactation: a case report. Journal of Clinical Sleep Medicine 14(12) (2018) 2087-2089. https://doi.org/10.5664/jcsm.7546
J.L. Chapman, A. Vakulin, J. Hedner, B.J. Yee, N.S. Marshal. Modafinil/armodafinil in obstructive sleep apnoea: a systematic review and meta-analysis. European Respiratory Journal 47 (2016) 1420-1428. https://doi.org/10.1183/13993003.01509-2015
H. Mai, E. Ranjbari, C. Gu, A.G. Ewing. Mass spectrometry imaging shows modafinil, a student study drug, changes the lipid composition of the fly brain. Angewandte Chemie International Edition 60 (2021) 17378-17382. https://doi.org/10.1002/anie.202105004
J.D. Keighron, J.B. Giancola, R.J. Shaffer, E.M. DeMarco, et al. Distinct Effects of (R)-Modafinil and its (R)- and (S)-Fluoro-Analogs on Mesolimbic Extracellular Dopamine Assessed by Voltammetry and Microdialysis in Rats. European Journal Neuroscience 5 (3) (2019) 2045-2053. https://doi.org/10.1111/ejn.14256
S. Assi, I. Kha, A. Edwards, D. Osselton, H. Al-Obaidi. On-spot quantification of modafinil in generic medicines purchased from the Internet using handheld Fourier transform infrared, near-infrared, and Raman spectroscopy. Journal of Analytical Science and Technology 11(35) (2020). https://doi.org/10.1186/s40543-020-00229-3
B. Ramachandra. A Critical Review of Properties of Modafinil and Analytical, Bioanalytical Methods for its Determination. Critical Reviews in Analytical Chemistry 46(6) (2016) 482-489. https://doi.org/10.1080/10408347.2016.1153948
S.P. Stokes, C.C. Seaton, K.S. Eccles, A.R. Maguire, S.E. Lawrence. Insight into the Mechanism of Formation of Channel Hydrates via Templating. Crystal Growth & Design 14 (2014) 1158 -1166. https://doi.org/10.1021/cg401660h
A. Ceausu, A. Lieberman, J. Aronhime. Crystalline forms of modafinil, United States No US 2005/0034652 A1, Feb. 17, 2005.
M. Pauchet, T. Morelli, S. Coste, J.J. Malandain, G. Coquerel. Crystallization of (±)-Modafinil in Gel: Access to Form I, Form III, and Twins. Crystal Growth & Design 6(8) ( 2006) 1881-1889. https://doi.org/10.1021/cg060203k
J. Mahieux, M. Sanselme, G. Coquere. Access to Single Crystals of (±)-Form IV of Modafinil by Crystallization in Gels. Comparisons between (±)-Forms I, III, and IV and (-)-Form I. Crystal Growth & Design 13 (2) (2013) 908-917. https://doi.org/10.1021/cg301630d
R. Kumar, M.A. Sheela, M. Sachdeva. Formulation and Evaluation of Orodispersible Tablets Containing Cocrystals of Modafinil. Journal of Drug Delivery & Therapeutics 12(5-S) (2022) 82-89. https://doi.org/10.22270/jddt.v12i5-s.5634
A. Sallam, I.I. Salem, D. AlJohari, M. Shawer, B. Abu Alaasal, D. Omari. Bioequivalence of Two Oral Formulations of Modafinil Tablets in Healthy Male Subjects under Fed and Fasting Conditions. Journal of Bioequivalence and Bioavailability 7 (2) (2015) 63-67. https://doi.org/10.4172/jbb.1000216
K. Adibkia, S. Selselehjonban, S. Emami, K. Osouli-Bostanabad, M. Barzegar-Jalali. Electrosprayed polymeric nanobeads and nanofibers of modafinil: preparation, characterization, and drug release studies. Bioimpacts 9 (3) (2019) 179-188. https://doi.org:/10.15171/bi.2019.22
T. Ghosh, T. Juturu, S.N. Nagar, S. Kamath. Cocrystals of Modafinil-Nicotinic Acid: A Novel Cocrystal for Enhanced Bioavailability. Proceedings 62(1) (2021) 12. https://doi.org/10.3390/proceedings2020062012
D. Ahuja, K.A. Ramisetty, P.K. Sumanth, C.M. Crowley, M. Lusi, Å.C. Rasmuson. Microwave assisted slurry conversion crystallization for manufacturing of new cocrystals of sulfamethazine and sulfamerazine. Crystal Engineering Community 22 (2020) 1381-1394 https://doi.org/10.1039/c9ce01886g
A. BeÌrziÅÅ, A. Trimdale, A. Kons, D. ZvaniÅa. Access to several polymorphic forms of (â±)-modafinil by using Various Solvation-Desolvation Processes. Crystal Growth & Design 17(11) (2017) 5712-5724. https://doi.org/10.1021/acs.cgd.5b01384
E. Joiris, P. Di Martino, C. Berneron, A.M. Guyot-Hermann, J.C. Guyot. Compression behavior of orthorhombic paracetamol. Pharmaceutical Research 15(7) (1998) 1122-30. https://doi.org/10.1023/a:1011954800246
F. Alakayleh, I. Rashid, M. M. Al-Omari, K. Al-Sou'od, B. Z. Chowdhry, A. A Badwan. Compression profiles of different molecular weight chitosans. Powder Technology 299 (2016) 107-118. https://doi.org/10.1016/j.powtec.2016.05.019
R. Kandasamy, C. Kumerasan. Effects of crystallinity on compression of pharmaceuticals. Pharmaceutical Times 43(10) (2011) 13-15.
H.A. Garekani, F. Sadeghi, A. Badiee, S.A. Mostafa, A.R. Rajabi-Siahboomi. Crystal Habit Modifications of Ibuprofen and Their Physicomechanical Characteristics. Drug Development and Industrial Pharmacy 27(8) (2001) 803-809. https://doi.org/10.1081/ddc-100107243
H. H. M. Ali, F. Al-Akayleh, A. H. Al Jafari, I. Rashid. Investigating Variation in Compressional Behavior of a Ternary Mixture from a Plastic, Elastic and Brittle Fracture Perspective in the Context of Optimum Composition of a Pharmaceutical Blend. Polymers 15(5) (2023) 1063. https://doi.org/10.3390/polym15051063
R. Ghadi, A. Ghuge, S. Ghumre, N. Waghmare, V.J. Kada. Cocrystals: Emerging Approach in Pharmaceutical Design. Indo American Journal of Pharmaceutical Research 4(7) (2014) 3881-3893. https://doi.org/10.3390/polym15051063
S. Jadhav, A. Mali. An Overview on Co-crystallisation. Inventi Rapid: Pharmaceutical Technology 2015(1) (2015) 15207.
A.V. Yadav, A.S. Shete, A.P. Dabke, P.V. Kulkarni, S.S. Sakhare. Cocrystals: A Novel Approach to Modify Physicochemical Properties of Active Pharmaceutical Ingredients. Indian Journal of Pharmaceutical Sciences 71 (4) (2009) 359-370. https://doi.org/10.4103/0250-474X.57283
N. Radacsi, J.H. ter Horst, G.D. Stefanidis. Microwave-Assisted Evaporative Crystallization of Niflumic Acid for Particle Size Reduction. Crystal Growth Design 13 (2013) 4186-4189. https://doi.org/10.1021/cg4010906
H.K. Solanki, V.D. Prajapati, G.K. Jani. Microwave Technology - A Potential Tool in Pharmaceutical Science. International Journal of Pharmaceutical Technology and Research 2 (3) (2010) 1754-1761.
T.W. Wong, Use of Microwave in Processing of Drug Delivery Systems, Current Drug Delivery 5 (2008) 77-84. https://doi.org/10.2174/156720108783954842
T.P. Holm, M.M. Knopp, K. Lobmann, R. Berthelsen, Microwave induced in situ amorphisation facilitated by crystalline hydrates, European Journal of Pharmaceutical Sciences 163 (2021) 105858, https://doi.org/10.1016/j.ejps.2021.105858
W. Qiang, K. Löbmann, C.P. McCoy, G.P. Andrews, M. Zhao, Microwave-Induced In Situ Amorphization: A New Strategy for Tackling the Stability Issue of Amorphous Solid Dispersions: A Review. Pharmaceutics 12 (2020) 1-19 https://doi.org/10.3390/pharmaceutics12070655
S.G. Gattani, S.L. Patwekar, Solubility and Dissolution Enhancement of Poorly Water-soluble Ketoprofen by Microwave-assisted Bionanocomposites: In Vitro and In Vivo Study. Asian Journal of Pharmaceutics (Suppl) 10(4) (2016) S601. https://doi.org/10.22377/ajp.v10i04.897
S. Alshehri, F. Shakeel, M. Ibrahim, E. Elzayat, M. Altamimi, G. Shazly, K. Mohsen, M. Alkholief, B. Alsulays, A. Alshetaili, A. Alshahrani, B. Almalki, F. Alanazi.Influence of the microwave technology on solid dispersions of mefenamic acid and flufenamic acid. PLoS ONE 12(7) (2017) e0182011. https://doi.org/10.1371/journal.pone.0182011
S. Pagire, S. Korde, R. Ambardekar, S. Deshmukh, R. Dash, R. Dhumal, A. Paradkar. Microwave assisted synthesis of caffeine/maleic acid cocrystals: the role of the dielectric and physicochemical properties of the solvent. Crystal Engineering Community 15 (2013) 3705-3710 https://doi.org/10.1039/c3ce40292d
N.J. Hempela, M.M. Knopp, J.A. Zeitler, R. Berthelsen, K. Lobmann. Microwave-Induced in Situ Drug Amorphization Using a Mixture of Polyethylene Glycol and Polyvinylpyrrolidone. Journal of Pharmaceutical Sciences 110 (2021) 3221-3229. https://doi.org/10.1016/j.xphs.2021.05.010
T.P. Holm, M. Kokott, M.M. Knopp, B.J. Boyd, R. Berthelsen, J. Quodbach, K. Löbmann. Development of a multiparticulate drug delivery system for in situ amorphisation. European Journal of Pharmaceutics and Biopharmaceutics 180 (2022) 170-180 https://doi.org/10.1016/j.ejpb.2022.09.021 .
J.R. Madan, A.R. Pawar, R.B. Patil, R. Awasthi, K. Dua. Preparation, characterization and in vitro evaluation of tablets containing microwave-assisted solid dispersions of apremilast. Polimers in Medicine 48(1) (2018) 17-24. https://doi.org/10.17219/pim/99801
T.P. Holm, M.M. Knopp, K. Lobmann, R. Berthelsen. Microwave induced in situ amorphisation facilitated by crystalline hydrates. European Journal of Pharmaceutical Sciences 163 (2021) 105858. https://doi.org/10.1016/j.ejps.2021.105858
D. Omari, A.A. Sallam, Use of Ultrasound and Microwaves to enhance solubility and bioavailability of Modafinil: Formulation and characterization of tablets for oral dosage form. Proceedings of EuroAnalysis 2019, Istanbul, Turkey [Abstract:0710] P3-029 (2020).
P. Patel, Y.K. Agrawal, J. Sarvaiya. Cyclodextrin based ternary system of modafinil: Effect of trimethyl chitosan and polyvinylpyrrolidone as complexing agents, International Journal of Biological Macromolecules 84 (2016) 182-188. https://doi.org/10.1016/j.ijbiomac.2015.11.075
M.J. Jacobs, B.T. Mcintyre, A. Parikh, P.R. Patel, Pharmaceutical solutions comprising a modafinil compound and their use for the manufacture of a medicament for treating different diseases, 2007, New Zealand Patent # NZ539778A. https://patents.google.com/patent/NZ539778A/en
B.N. Aldosari, A.S. Almurshedi, I.M. Alfagih, B.T. AlQuadeib, M.A. Altamimi, S.S. Imam, A. Hussain, F. Alqahtani, E. Elzayat, S. Alshehri. Formulation of Gelucire®-Based Solid Dispersions of Atorvastatin Calcium: In Vitro Dissolution and In Vivo Bioavailability Study, AAPS Pharmaceutical Science and Technology 22(5) (2021) 161. https://doi.org/10.1208/s12249-021-02019-5 Correction: AAPS Pharmaceutical Science and Technology 23(7) (2022) 278. https://doi.org/10.1208/s12249-021-02019-5
I. Al-Naji, F. Al-Akayleh, R. Al-Ajeeli, N.A. Qinna, M. Al-Remawi, M. Khanfar, A.S. Sallam. Chitosan/Alginate/Gelucire in-situ Gelling System for Oral Sustained Delivery of Paracetamol for Dysphagic Patients. Jordan Journal of Pharmaceutical Sciences 17(2) (2024) 292-306. https://doi.org/10.35516/jjps.v17i2.1702
S. Alshehri, F. Shakeel, M. Ibrahim, E. Elzayat, M. Altamimi, G. Shazly, K. Mohsin, M. Alkholief, B. Alsulays, A. Alshetaili, A. Alshahrani, B. Almalki, F. Alanazi. Influence of the microwave technology on solid dispersions of mefenamic acid and flufenamic acid. PLoS One 12(7) (2017) https://doi.org/10.1371/journal.pone.0182011
M.A. Momoh, F.C. Kenechukwu, C.S. Nwagwu, P. Uuzor, V. Obieze, A. Nafiu, O. James, A. Ofomatah, A. isah, S. M. Salihu. Formulation and In Vitro Characterization of Ibuprofen-Loaded Solid Dispersions. African Journal of Pharmaceutical Research and Development 12(1) (2020) 56-69. https://www.researchgate.net/publication/341967023
Gelucire® 48/16 pellets Solubility and oral bioavailability enhancement. https://www.pharmaexcipients.com/wp-content/uploads/2020/03/Gelucire-48-16_solubility-and-bioavailability-enhancer-from-Gattefosse.pdf acssessed March 2024.
M. Bentolila, A. Shusterman, M. Arkin, J. Kaspi, modafinil formulations, 2004,US Patent No US 2004/0105891 A1, Jun. 3. https://patentimages.storage.googleapis.com/ea/50/e6/67c5bea9f7797a/US20040105891A1.pdf
M. Shawer, A.A. Salam, D. Jawhari. Formulation and process for the preparation of modafinil, 2012,US Patent No: US 8,173,169 B2, May 8. https://patents.google.com/patent/US8173169B2/en
V. Corvari, G. Grandolfi, A. Parikh. Pharmaceutical formulations of modafinil, 2007, US Patent No: US7297346B2. https://patents.google.com/patent/US7297346B2/en
L. Cai, L. Farber, D. Zhang, F. Li, J. Farabaugh. A new methodology for high drug loading wet formulation development. International Journal of Pharmaceutics 441 (2013) 790-800. https://doi.org/10.1016/j.ijpharm.2012.09.052
M. Mothilal, A. Kumar, M.C. Krishna, V. Manasa, V. Manimaran, N. Damodharan, Formulation and Evaluation of Modafinil Fast Dissolving Tablets by Sublimation Technique, Journal of Chemical and Pharmaceutical Sciences 6 (3) (2013) 147-154. https://www.researchgate.net/publication/287870059
I. Rashid, R.R. Haddadin, A.A. Alkafaween, R.N. AlKaraki, M. Alkasasbeh. Understanding the implication of Kawakita model parameters using in-die force-displacement curve analysis for compacted and noncompacted API powders. AAPS Open 8(6) (2022) 6. https://doi.org/10.1186/s41120-022-00053-6
F. Al-Akayleh, A. M. Mustafa, M. Shubair, H. S. AlKhatib, I. Rashid, A. Badwan. Development and evaluation of a novel, multifunctional, coprocessed excipient via roller compaction of α-Lactose Monohydrate and Magnesium Silicate. Journal of Excipient and Food Chemicals 4 (2016) 1086.
M. Inoue, I. Hirasawa. The relationship between crystal morphology and XRD peak intensity on CaSO4·2H2O. Journal of Crystal Growth 380 (2013) 169-175. https://doi.org/10.1016/j.jcrysgro.2013.06.017
D. Sherwood, J. Cooper. Crystals, x-rays and proteins: comprehensive protein crystallography, Oxford University Press 68 (1) (2012) 93-132. https://doi.org/10.1107/S0907444911051456
S. Selvaraj, P. Rajkumar, M. Kesavan, K. Thirunavukkarasu, S. Gunasekaran, N. Saradha Devi, S. Kumaresan. Spectroscopic and structural investigations on modafinil by FT-IR, FT-Raman, NMR, UV-Vis and DFT methods. Spectrochim Acta A Molecular and Biomolecular Spectroscopic 224 (2020) 117449. https://doi.org/10.1016/j.saa.2019.117449
P. Gill, T.T. Moghadam, B. Ranjbar, Differential scanning calorimetry techniques: applications in biology and nanoscience. Journal of Biomolecular Technology 21(4) (2020) 167-193. https://typeset.io/pdf/differential-scanning-calorimetry-techniques-applications-in-7ozkshrju8.pdf
C. Leyva-Porras, P. Cruz-Alcantar, V. Espinosa-Solís, E. Martínez-Guerra, C.I. Piñón-Balderrama, I. Compean Martínez, M.Z. Saavedra-Leos, Application of Differential Scanning Calorimetry (DSC) and Modulated Differential Scanning Calorimetry (MDSC) in Food and Drug Industries. Polymers 12 (2020) 5. https://doi.org/10.3390/polym12010005
J.W. Lee, L.C. Thomas, S.J. Shmirt. Investigation of the heating rate dependency associated with the loss of crystalline structure in sucrose, glucose, and fructose using a thermal analysis approach (Part I). Journal of Agriculture and Food Chemistry 59(2) (2010) 684–701. https://doi.org/10.1021/jf1042344
J.W. Lee, L. Thomas, J. Jerrell, H. Feng, K.R. Cadwallader. Investigation of Thermal Decomposition as the Kinetic Process That Causes the Loss of Crystalline Structure in Sucrose Using a Chemical Analysis Approach (Part II). Journal of Agriculture and Food Chemistry 59(2) (2010) 702-712. https://doi.org/10.1021/jf1042344d
Y. Lu, L. Yin, D. L. Grey, L. C. Thomas, S.J. Shmidt. Impact of Sucrose Crystal Composition and Chemistry on its Thermal Behavior. Journal of Food Engineering 214 (2017) 193-208. https://doi.org/10.1016/j.jfoodeng.2017.06.016
M. Doumeng, L. Makhlouf, F. Berthet, O. Marsan, K. Delbé, J. Denape, F. Chabert, A comparative study of the crystallinity of polyetheretherketone by using density, DSC, XRD, and Raman spectroscopy techniques, Polymer Testing 93 (2021) 106878. https://doi.org/10.1016/j.polymertesting.2020.106878
M. Khanfar, M. Al-Remawi, F. Al-Akayleh, S. Hmouze. Preparation and evaluation of co-amorphous formulations of telmisartan—amino acids as a potential method for solubility and dissolution enhancement. AAPS PharmSciTech 22(3) (2021) 112. https://doi.org/10.1208/s12249-021-01952-9
D.J. Blundell, B.N. Osborn. The morphology of poly(aryl-ether-ether-ketone). Polymer 24 (1983) 953-958. https://doi.org/10.1016/0032-3861(83)90144-1
P.J. Holdsworth, A. Turner-Jones, The melting behaviour of heat crystallized poly(ethylene terephthalate). Polymer 12 (1970) 195-208. https://doi.org/10.1016/0032-3861(71)90045-0
J.M.G. Cowie, V. Arrighi. Polymers chemistry and physics of modern materials. 2nd ed. 1991, Blackie Academic & Professional, London, UK, pp. 279-318. ISBN: 978-0748740734
D. Abu Fara, L. Al-Hmoud, I. Rashid, B.Z. Chowdhry, A. Badwan. Understanding the Performance of a Novel Direct Compression Excipient Comprising Roller Compacted Chitin. Marine Drugs 18(2) (2020) 115. https://doi.org/10.3390/md18020115
M.J. Muthu, K. Kavitha, K.S. Chitra, S. Nandhineeswari. Soluble curcumin prepared by solid dispersion using four different carriers: phase solubility, molecular modelling and physicochemical characterization. Tropical Journal of Pharmaceutical Research 18(8) ((2019) 1581-1588. http://dx.doi.org/10.4314/tjpr.v18i8.2
S. Bertoni, B. Albertini, N. Passerini. Different BCS Class II Drug-Gelucire Solid Dispersions Prepared by Spray Congealing: Evaluation of Solid State Properties and In Vitro Performances. Pharmaceutics 12(6) (2020) 548. Https://doi.org/10.3390/pharmaceutics12060548
P. Upadhyay, J.K. Pandit. Formulation of Fast-Release Gastroretentive Solid Dispersion of Glibenclamide with Gelucire 50/13. Tropical Journal of Pharmaceutical Research 11(3) (2012) 361-369. http://dx.doi.org/10.4314/tjpr.v11i3.4
R. Lalge, R. Lalge, P. Thipsay, V.K. Shankar, A. Maurya, M. Pimparade, S. Bandari, F. Zhang, S.N. Murthy, M.A. Repka. Preparation and Evaluation of Cefuroxime Axetil Gastro-Retentive Floating Drug Delivery System for Improved Delivery via Hot-Melt Extrusion Technology. Internation Journal of Pharmaceutics 566 (2019) 520-531. https://doi.org/10.1016/j.ijpharm.2019.06.021
M. Mohan, M. Mothilal, A. Kumar, M. Krishna, V. Manasa, V. Manimaran, N. Damodharan. Formulation and evaluation of modafinil fast dissolving tablets by sublimation technique. Journal of Chemical and Pharmaceutical Sciences 6 (2013) 147-154.
©2025 by the authors; licensee IAPC, Zagreb, Croatia. This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/)