INTRODUCTION:

In the early 2000s, Co-Amorphous (COAM) system started to attract interest. To accelerate the dissolution rate of medication that aren’t highly soluble in water, researchers began to investigate the manufacturing of COAM blends ¹. Initially researchers began to explore a wider range of coformers, not limited to saccharin, and identified various COAM systems with the development of advanced Assessment techniques like solid-state NMR and X-ray diffraction have become, and Thermal examination, researchers gained better perspective on the formation and stability of COAM systems.² In the Pharma sector, COAM formulations have become more

popular as approach of increasing the biological availability of insoluble substances medications.

In order to develop effective medications with appropriate dosage schedules for patients, pharmaceutical companies have begun to concentrate on enhancing the solubility and dissolution of certain medications to increase their bioavailability.³

This is because the majority of new drugs that are under development have poor solubility in water, which is related to numerous pharmaceutical issues.⁴ Throughout the previous ten years, a increasing quantity of research reports on the examination of co-amorphous ways to deliver drugs have been produced, which leads to noteworthy and hopeful enhancements to the in-animal and in-laboratory performances of weakly soluble therapeutics.⁵ Amorphous drugs are primarily described as those that are extremely soluble in water and have lesser stability. Conformers are substances that have a crystalline structure and consist of at least two individual molecules. These molecules typically form as Cocrystal and API, which have the same precise stoichiometry and crystallize in the same crystal lattice.⁶ A co-amorphous system is composed of two drug molecules that stabilize both of them in a translucent form. This type of system exhibits a high rate of solubility, stability, and dissolution⁷. Solid dispersion technology is the most comprehensive method of stabilizing amorphous forms. It involves incorporating a medication into an amorphous polymer to raise the system's glass phase conversion temperature) and give it stability.⁸ First of all, Drug-polymer mixtures are frequently moisture absorptive in this scenario, the moisture absorbed lowers the system's glass transition temperature (TG), which causes layer separation and calcinations. Secondly, substantial amounts of polymer are frequently needed for adequate drug loading owing to the limited compatibility of particular medications in the polymer, resulting in enormous more quantity of complete dosage forms.⁹ Therefore, to effectively stabilize the amorphous form of pharmaceuticals, a unique approach to amorphous polymer dispersion is needed, step by step. The idea of co-amorphous systems has been presented as a solution to several issues with solid dispersion technology. Instead of using drug-polymer combinations, two small molecules (drugs or excipients) are combined in these systems. It has been discovered that these systems offer the medications great stability and improved rates of disintegration. The two medications in the system's solid-state interactions have been identified as the main cause of the increased stability and disintegration. In terms of cocrystals, a 3-dimensional ordering into a crystal lattice must arise from the interactions between the coformer molecules and the API. On the other hand, the mixture of API and polymer ought to exist in a single phase and function as a meta-stable amorphous "solid solution"¹⁰

Figure. 1. Co-amorphous System

When an API is molecularly dispersed in an amorphous polymer, such as polyvinylpyrrolidone or cellulose-based polymers, which function as inactive stabilizers, amorphous solid dispersions are created.¹¹Reduced molecular mobility is the result of the polymer's formation of intermolecular contacts and raising the glass transition temperature, which causes stabilization.Two primary obstacles to using amorphous solid dispersions are: first, their huge polymer to API mass ratios, which can lead to issues with downstream formulation when high API dosages are needed, and their high hygroscopicity, which increases the molecular mobility of the API.¹² An API and a low-molecular-weight substance known as a co-former—which is typically inactive but might alternatively be another API—are combined to develop COAM systems. When there is a particularly high ratio of API to conformer, high-API-dose tablets can be created. COAM systems, like co-crystals, are usually made up of two parts: an API and a co-former.¹³ The difference between COAM systems and co-crystals is that the latter have an amorphous structure without repeating units, while the former are constructed on a three-dimensional crystal lattice that repeats. Based on their constituent parts, co-amorphous systems can be divided into three primary groups: solid dispersions, drug-drug mixtures, and drug-excipient combinations.

Fig. 2. Classification of solid dispersion¹⁴

1. Drug-Drug mixture: Two medications linked to pharmacology have been stabilized. Less excipients and improved patient compliance are the outcomes of administering medications simultaneously in a single-dose unit.¹⁵ Furthermore, both medications have enhanced solubility and dissolving rate, as demonstrated by the synchronized release of pharmaceuticals like naproxen and indomethacin.

2. Drug-Excipient combination: Amino acids (AAs) are employed in these systems as biocompatible co-formers that increase the TG and function as anti-plasticizers by preventing drug-drug interactions and postponing recrystallization. Compared to polymeric SDs, only minimal quantities are needed because of the low MW. The choice of AAs is influenced by knowledge of putative drug-receptor interactions at the biological binding site. Reportedly, chemical interactions such as those between dipyridamole and p-hydroxybenzoic acid give co-amorphous drug-AA systems a better physical stability and dissolution rate than amorphous pharmaceuticals.¹⁶

3. Solid Dispersion: The amorphous medication is stabilized, and its solubility and rate of dissolution are increased by using polymeric carriers.¹⁷ Itraconazole and fumaric acid are two examples of drugs that are molecularly distributed in an amorphous polymer below their limit of solubility and are stabilized by the physical separation of the molecules between the polymer chains.

METHODS OF FORMULATION:

Different methods are used for creating COAM systems, and there are various kinds of co-amorphization preparation techniques are given below and prepared formulations are listed with the drug and the coformer used with methods of formulation.

1) Solvent Evaporation: Typically, crystalline components are dissolved in a normal organic solvent, which is then heated or evaporated under vacuum, to create co-amorphous SDs. To ensure that there are no leftovers, we dry for at least twenty-four hours.¹⁸ Since the solvent is withdrawn so quickly, the molecules are dissolved in the co-amorphous system via co-precipitation, leaving no time for them to reorganise in a crystal lattice¹⁹.

2) Milling: The most often used approach is milling, which uses mechanical activation to change materials into an amorphous form. This is because it's easy to handle. It also shows comparatively excellent yield recovery and minimal chemical degradation. Notwithstanding these benefits, the process is labor-intensive, time-consuming, and prone to leaving behind crystalline impurities that might contaminate the combination.²⁰

i. Ball Milling: It is a popular method for creating nanoparticles. It has the ability to create nanoparticles with precise size and characteristics. It is a mechanical method for enhancing material properties and lowering particle size. It involves employing a rotating container, typically made of steel or ceramic, that is filled with balls.²¹ It is widely used in a variety of fields, including materials research, nanotechnology, and medicine. Ball milling works on the basis of the material to be processed and a container loaded with balls. The material is struck by the balls while the container spins, reducing the size of the particles and mechanically grinding them. The material's physical and chemical characteristics may alter as a result of the impact and friction forces produced during ball milling. There are many energy levels at which high-energy ball milling may be performed. This method works well for both material modification and synthesis.

ii. Cryo Milling: A size-reduction technique specifically designed for soft, elastic/plastic, non-brittle, and thermolabile materials are called cryogenic milling, or cryomilling for short. There are two ways to do cryomilling: either freeze the materials in liquid nitrogen (-100 to -150°C) before milling them or mill the materials in liquid nitrogen while under cryogenic conditions. Exposed to liquid nitrogen, the material undergoes "embrittlement," which facilitates the propagation of fractures, reduces the specific energy required for milling, and potentially expedites the milling process.²² Even though it accomplishes the same goal and produces brittle and porous materials, freeze drying is better suited for liquids or solids with higher residual moisture levels since it is a drying process.

3) Quench Cooling: The drug combination is heated initially in the quench cooling procedure, and the molten drug is then quickly cooled. It remains amorphous because the cooling period is kept brief enough to prevent molecules from reorganizing into a crystalline lattice.²³ For the production of small-quantity ASD formulations, quench cooling is helpful, especially for thermostable medications. Nevertheless, there are several disadvantages to this method, such as the requirement for tight control over the freezing rate and the potential chemical deterioration of the components²⁴.

4) Freeze Drying: Primary drying, secondary drying, and freezing are the three main steps in the freeze-drying process. Out of all of them, primary drying is seen as the most crucial step since it mostly affects how long the processing will take overall and how good the finished product will be. Therefore, the main focus of lyophilization condition optimization is on the first drying step.²⁵ The clear solution was effectively lyophilized under ideal circumstances, particularly during the initial drying step, to obtain fluffy co-amorphous powder. The freeze-dried CAM exhibited exceptional chemical and physical stability and formed a heterodimer.²⁶

5) Spray Drying: The pharmaceutical industry was the first to adopt spray drying to produce pure API. Since then, it has been used more and more in specialized formulations, including liposomes, microcapsules, and nanoparticles.²⁷ Additionally, spray drying might be used to create CAM, which is simple to scale up²⁸^-²⁹. The spray drying technique consists of two steps: nebulization and drying.In the nebulization stage, a heated chamber is sprayed with mist droplets containing the component solution.The droplets continue their outward movement and solvent elimination during the drying stage, producing particles with the perfect size and shape.³⁰

6) HME (Hot Melt Extrusion): One technique for improving the solubility, bioavailability, and dissolution of API with low aqueous solubility is hot melt extrusion. A 3.0 mm die is used with a twin-screw extruder that has a screw diameter of 16 mm and a length of 40 mm (640 mm). Powder mixes are supplied to the extruder barrel using a loss-in-weight powder feeder after being mixed for 20 minutes at 50 rpm using a Turbula® T2A mixer. A powder batch should weigh between 300 and 500 grams. The medicine is added to the extruder barrel using a peristaltic pump via a 2.4-mm inner-diameter nozzle after it has been dissolved in demineralized water at 70 degrees Celsius.³¹^,

Table 1: Drug-Drug Binary Formulation:

Sr. No	Drugs	Conformer	Method	Ref.
1	Simvastatin	Nifidepine	Cryogenic Milling Ball Milling	32
2	Atrovastatin	Irbesartan	Quench Cooling	33
3	Indomethacin	Nimesulide	Quench Cooling	34
4	Curcumin	Artemisinin	Solvent Evaporation	35
5	Naproxen	Indomethacin	Spray Drying	36
6	Curcumin	Piperazine	Liquid Assisted Grinding	37
7	Atrovastatin	Glipizide	Cryomilling	38
8	Docetoxel	bicalutamide	Ball milling	39

Table 2. Drug Amino acids binary formulation:

Sr. No	Drug	Amino acids	Methods	Ref.
1	Quercetin	Arginine	Ball milling	40
2	Grisiofulvin	Tryptophan	Ball milling	41
3	Ofloxacin	Tryptophan	Lyophilization	42
4	Glibenclamide	Serine and Arginine	Cryomilling	43
5	Telmisartan	Arginine	Freeze drying	44
6	Valsartan	L-histidine,l-Arginine, and l-lysine	Vibration ball milling	45

Table 3: Solid Dispersion

Sr. No	Drug- Polymer	Third Ingredient	Methods	Ref.
1	Lurasidone-Poloxamer 188	Fluorite	Fusion method	46
2	Itraconazole- HPMCP	Soluplus	Hot melt extrusion	47
3	Chlorthalidone -Soluplus	SLS	Spray dried	48
4	Ezetimibe- PVP K30	Poloxamer 188	Melt quenching	49
5	Carbamazepine-Kollidon® VA64	Neusilin UFL2	Rotary evaporation	50

Table 4. Drug-surfactants:

Sr. No	Drugs	Surfactant	Methods	Ref.
1	Ibrutinib–Oxalic acid	Microcrystalline cellulose	Ball milling	51
2	Ritonavir –Darunavir	HPMC/ PVP/ HP- β-CD	Spray drying	52
3	Hydrochlorothiazide– Arginine	PVP	Cryo-milling	53
4	Sacubitril–Valsartan	Microcrystalline cellulose	Spray drying	54
5	Carvedilol–Aspartic acid	HPMC	Spray drying	55
6	Flutamide–Bicalutamide	PMMAEA	Melt-quench	56

SOLID STATE CHARACTERIZATION:

Co-amorphous system identification has been established in the initial stage of crystal development methods, which makes solid state identification important for stability studies and verification of co-amorphous formation.

1. X-ray Powder Diffraction (XRP): Among the three ways of x-ray diffraction, the powder method (the Laue photographic method, the Braggs X-ray spectrometer method, and the rotating crystal method) is the most effective. Here, we may collect a small sample size (about 1 mg) for analysis. The specimen is exposed to the whole X-ray beam along the cylindrical camera's axis, which is encircled by a circular arc of powder crystal. It is held in place by a piece of gum on the hair. Through slits, the x-ray beam is directed onto the specimen. The photographic plate displays patterns made out of remains.⁵⁷

2. Raman Spectroscopy: Understanding the solid-state interactions between the medication and the excipient in co-amorphous systems by Raman spectroscopy can aid in understanding the stabilisation processes.¹⁶ Using Raman imaging spectroscopy phase separation is investigated as near as feasible, the same precise and labelled location within the samples should be used for each subsequent measurement. The time between measurements is shorter for PAR-TRF because it crystallized more quickly than the other mixes⁵⁸

3. Differential Thermal Analysis (DTA): It is a kind of thermal analysis technique where a substance's physical characteristics whenever the chemical is subject to an established temperature-program, is evaluated in regard to temperature. Here, in DTA, a standard equipment setup is used. Heat is applied to the sample (S) and reference (R) metal cups at a steady pace, and the thermocouple junction measures the temperature difference, or AT (TS TR) The sample temperature changes endothermically, as indicated by the heating curve and differential heating curve, producing typical differential traces until the sample experiences an enthalpic transition.⁵⁹

4. Fourier transforms Infrared Spectroscopy (FTIR): It is a useful technique for examining the molecules' adjacent in co-amorphous mixtures. Fourier transforms infrared, or FTIR, is the preferred infrared (IR) spectroscopic technique. IR radiation is transmitted through a sample in infrared spectroscopy. Portion of the infrared spectrum penetrates through the sample, whereas a bit of it flows through. The resulting spectrum, leading to molecule absorption and transmission, which provides a molecular fingerprint of the compound.⁶⁰

5. Differential Scanning: Calorimetry These thermal analysis measures the difference in heat required to improve the temperature of a specimen relative to a reference, as a function of temperature. The specimen and reference temperatures are kept nearly constant throughout the experiment. The temperature is usually adjusted for a DSC-Research such that the temperature of the sample holder gradually increases with time. The heating ability of the reference sample has to be carefully calculated across the temperature range that will be examined. Furthermore, the reference sample needs to be highly pure and stable and not significantly vary throughout the temperature scan. Reference standards usually contain lead, bismuth, tin, and indium.

DISCUSSION AND CONCLUSION:

In comparison with a single amorphous or tablet formulation, COAM formulation is a promising way to improve a number of formulation properties, including drug solubility, dissolution, physical stability, bioavailability, and good formulation flexibility, all of which have an impact on patient acceptability. COAM formulations can also be advantageous from a competitive point of view in the pharmaceutical industry. In the modern pharmaceutical business, the development of COAM systems through the use of excipients, small amounts of API, coformers, and polymers is an innovative step towards a brighter future in the medical profession that improves patient outcomes. Currently, a number of scientific, financial, and medical considerations are driving the co-amorphous formulation industry in medicines to increase compliance.

CONFLICT OF INTEREST:

The authors declare no conflicts of interest.

ACKNOWLEDGMENTS:

The authors extend their sincere gratitude to Samarth College of Pharmacy for their invaluable guidance and support throughout this study.

REFERENCES:

1. Shi, Q., Moinuddin, S. M. and Cai, T. Advances in coamorphous drug delivery systems. Acta Pharm. Sin. B. 2019; 9: 19–35. DOI:10.1016/j.apsb.2018.08.002.

2. Trasi, N. S., Bhujbal, S. V., Zemlyanov, D. Y., Zhou, Q. (Tony) and Taylor, L. S. Physical stability and release properties of lumefantrine amorphous solid dispersion granules prepared by a simple solvent evaporation approach. Int. J. Pharm. X 2020; 2. DOI:10.1016/j.ijpx.2020.100052.

3. Carrière, F. Impact of gastrointestinal lipolysis on oral lipid-based formulations and bioavailability of lipophilic drugs. Biochimie. 2016; 125: 297–305. DOI:10.1016/j.biochi.2015.11.016.

4. Kalepu, S. and Nekkanti, V. Insoluble drug delivery strategies: Review of recent advances and business prospects. Acta Pharm. Sin. B 2015; 5: 442–453. DOI:10.1016/j.apsb.2015.07.003.

5. Davis, M. and Walker, G. Recent strategies in spray drying for the enhanced bioavailability of poorly water-soluble drugs. Journal of Controlled Release. 2018; 269: 110–127. DOI:10.1016/j.jconrel.2017.11.005.

6. Gadade, D. D. and Pekamwar, S. S. Pharmaceutical cocrystals: Regulatory and strategic aspects, design and development. Advanced Pharmaceutical Bulletin. 2016; 6: 479–494. DOI:10.15171/apb.2016.062.

7. Chavan, R. B., Thipparaboina, R., Kumar, D. and Shastri, N. R. Co amorphous systems: A product development perspective. International Journal of Pharmaceutics. 2016; 515: 403–415. DOI:10.1016/j.ijpharm.2016.10.043.

8. Vasconcelos, T., Sarmento, B. and Costa, P. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discovery Today. 2007: 12: 1068–1075. DOI:10.1016/j.drudis.2007.09.005.

9. Laitinen, R., Lob̈mann, K., Strachan, C. J., Grohganz, H. and Rades, T. Emerging trends in the stabilization of amorphous drugs. International Journal of Pharmaceutics. 2013; 453: 65–79. DOI:10.1016/j.ijpharm.2012.04.066.

10. Newman, A., Reutzel-Edens, S. M. and Zografi, G. Coamorphous Active Pharmaceutical Ingredient–Small Molecule Mixtures: Considerations in the Choice of Coformers for Enhancing Dissolution and Oral Bioavailability. J. Pharm. Sci. 2018; 107: 5–17. DOI:10.1016/j.xphs.2017.09.024.

11. Nielsen, L. H., Rades, T. and Müllertz, A. Stabilisation of amorphous furosemide increases the oral drug bioavailability in rats. Int. J. Pharm. 2015; 490: 334–340. DOI:10.1016/j.ijpharm.2015.05.063.

12. Bhandare, R., Londhe, V., Ashames, A., Shaikh, N. and Alabdin, S. Z. Enhanced solubility of microwave-assisted synthesized acyclovir co-crystals. Res. J. Pharm. Technol. 2020; 13: 5979–5986. DOI:10.5958/0974-360X.2020.01043.4.

13. Karimi-Jafari, M., Padrela, L., Walker, G. M. and Croker, D. M. Creating cocrystals: A review of pharmaceutical cocrystal preparation routes and applications. Crystal Growth and Design. 2018; 18: 6370–6387. DOI:10.1021/acs.cgd.8b00933.

14. Punitha, S., Srinivasa Reddy, G., Srikrishna, T. and Lakshman Kumar, M. Solid dispersions: A review. Res. J. Pharm. Technol. 2011 4, 331–334 DOI:10.33786/jcpr.2010.v01i01.016.

15. Pilcer, G. and Amighi, K. Formulation strategy and use of excipients in pulmonary drug delivery. Int. J. Pharm. 2010; 392: 1–19. DOI:10.1016/j.ijpharm.2010.03.017.

16. Karagianni, A., Kachrimanis, K. and Nikolakakis, I. Co-amorphous solid dispersions for solubility and absorption improvement of drugs: Composition, preparation, characterization and formulations for oral delivery. Pharmaceutics. 2018; 10. DOI:10.3390/pharmaceutics10030098.

17. Psimadas, D., Georgoulias, P., Valotassiou, V. and Loudos, G. Molecular Nanomedicine Towards Cancer : J. Pharm. Sci. 2012; 101: 2271–2280. DOI:10.1002/jps.

18. Löbmann, K. et al. Co-amorphous simvastatin and glipizide combinations show improved physical stability without evidence of intermolecular interactions. Eur. J. Pharm. Biopharm. 2012; 81: 159–169. DOI:10.1016/j.ejpb.2012.02.004.

19. Sharma, D., Soni, M., Kumar, S. and Gupta, G. D. Solubility Enhancement-Eminent Role in Poorly Soluble Drugs. Res. J. Pharm. Tech. 2009; 2: 220–224.

20. Wang, H. et al. A review of process intensification applied to solids handling. Chem. Eng. Process. - Process Intensif. 2017; 118: 78–107. DOI:10.1016/j.cep.2017.04.007.

21. Sumanth Kumar, D., Jai Kumar, B. and Mahesh, H. M. Quantum Nanostructures (QDs): An Overview. Synthesis of Inorganic Nanomaterials: Advances and Key Technologies. 2018 doi:10.1016/B978-0-08-101975-7.00003-8 DOI:10.1016/B978-0-08-101975-7.00003-8.

22. Ye, J. and Schoenung, J. M. Technical cost modeling for the mechanical milling at cryogenic temperature (cryomilling). Adv. Eng. Mater. 2004; 6: 656–664 DOI:10.1002/adem.200400074.

23. D’Angelo, A., Edgar, B., Hurt, A. P. and Antonijević, M. D. Physico-chemical characterisation of three-component co-amorphous systems generated by a melt-quench method. J. Therm. Anal. Calorim. 2018; 134: 381–390. DOI:10.1007/s10973-018-7291-y.

24. Bhore, S. D. A review on solid dispersion as a technique for enhancement of bioavailability of poorly water soluble drugs. Res. J. Pharm. Technol. 2014; 7: 1485–1491.

25. Ohori, R., Akita, T. and Yamashita, C. Mechanism of collapse of amorphous-based lyophilized cake induced by slow ramp during the shelf ramp process. Int. J. Pharm. 2019 564, 461–471 DOI:10.1016/j.ijpharm.2019.04.057.

26. Silambarasan, I. and Rajalakshmi, A. N. A Review on Freeze-drying: A Stability Enhancement Technique. Res. J. Pharm. Technol. 2022; 15: 4841–4846. DOI:10.52711/0974-360X.2022.00813.

27. Singh, A. and Van den Mooter, G. Spray drying formulation of amorphous solid dispersions. Advanced Drug Delivery Reviews. 2016; 100: 27–50. DOI:10.1016/j.addr.2015.12.010.

28. Lenz, E. et al. Solid-state properties and dissolution behaviour of tablets containing co-amorphous indomethacin-arginine. Eur. J. Pharm. Biopharm. 2015; 96: 44–52. DOI:10.1016/j.ejpb.2015.07.011.

29. Dengale, S. J. et al. Preparation and characterization of co-amorphous Ritonavir–Indomethacin systems by solvent evaporation technique: Improved dissolution behavior and physical stability without evidence of intermolecular interactions. Eur. J. Pharm. Sci. 2014; 62: 57–64. DOI:10.1016/j.ejps.2014.05.015.

30. Sunitha Reddy, M., Shruthi, B., Mounika, B. and Sowmya, G. Fast dissolving drug delivery system - A Review. Res. J. Pharm. Technol. 2013; 6: 4–11.

31. Lenz, E., Löbmann, K., Rades, T., Knop, K. and Kleinebudde, P. Hot Melt Extrusion and Spray Drying of Co-amorphous Indomethacin-Arginine With Polymers. J. Pharm. Sci. 2017; 106: 302–312. DOI:10.1016/j.xphs.2016.09.027.

32. Loh, Z. H., Samanta, A. K. and Sia Heng, P. W. Overview of milling techniques for improving the solubility of poorly water-soluble drugs. Asian Journal of Pharmaceutical Sciences. 2014; 10: 255–274. DOI:10.1016/j.ajps.2014.12.006.

33. Skotnicki, M. et al. Physicochemical characterization of a co-amorphous atorvastatin-irbesartan system with a potential application in fixed-dose combination therapy. Pharmaceutics. 2021; 13: 1–20. DOI:10.3390/pharmaceutics13010118.

34. Wang, M. et al. Exploring the physical stability of three nimesulide–indomethacin co-amorphous systems from the perspective of molecular aggregates. Eur. J. Pharm. Sci. 2020; 147: 105294. DOI:10.1016/j.ejps.2020.105294.

35. Mannava, M. K. C., Suresh, K., Bommaka, M. K., Konga, D. B. and Nangia, A. Curcumin-artemisinin coamorphous solid: Xenograft model preclinical study. Pharmaceutics. 2018; 10. DOI:10.3390/pharmaceutics10010007.

36. Beyer, A. et al. Preparation and recrystallization behavior of spray-dried co-amorphous naproxen-indomethacin. Eur. J. Pharm. Biopharm. 2016; 104: 72–81. DOI:10.1016/j.ejpb.2016.04.019.

37. Pang, W. et al. Preparation of Curcumin-Piperazine Coamorphous Phase and Fluorescence Spectroscopic and Density Functional Theory Simulation Studies on the Interaction with Bovine Serum Albumin. Mol. Pharm. 2017; 14: 3013–3024. DOI:10.1021/acs.molpharmaceut.7b00217.

38. Renuka, Singh, S. K., Gulati, M. and Narang, R. Stable amorphous binary systems of glipizide and atorvastatin powders with enhanced dissolution profiles: formulation and characterization. Pharm. Dev. Technol. 2017; 22: 13–25. DOI:10.3109/10837450.2015.1125921.

39. Bohr, A. et al. Efflux inhibitor bicalutamide increases oral bioavailability of the poorly soluble efflux substrate docetaxel in co-amorphous anti-cancer combination therapy. Molecules 2019; 24: 1–13. DOI:10.3390/molecules24020266.

40. Hatwar, P., Pathan, I. B., Chishti, N. A. H. and Ambekar, W. Pellets containing quercetin amino acid co-amorphous mixture for the treatment of pain: Formulation, optimization, in-vitro and in-vivo study. J. Drug Deliv. Sci. Technol. 2021; 62: 102350. DOI:10.1016/j.jddst.2021.102350.

41. França, M. T., Marcos, T. M., Pereira, R. N. and Stulzer, H. K. Could the small molecules such as amino acids improve aqueous solubility and stabilize amorphous systems containing Griseofulvin? Eur. J. Pharm. Sci. 2020; 143: 105178 DOI:10.1016/j.ejps.2019.105178.

42. Zhu, S., Gao, H., Babu, S. and Garad, S. Co-Amorphous Formation of High-Dose Zwitterionic Compounds with Amino Acids to Improve Solubility and Enable Parenteral Delivery. Mol. Pharm. 2018; 15: 97–107. DOI:10.1021/acs.molpharmaceut.7b00738.

43. Heng, W. et al. Incorporation of Complexation into a Coamorphous System Dramatically Enhances Dissolution and Eliminates Gelation of Amorphous Lurasidone Hydrochloride. Mol. Pharm. 2020; 17: 84–97 DOI:10.1021/acs.molpharmaceut.9b00772.

44. Patel, J., Kevin, G., Patel, A., Raval, M. and Sheth, N. Design and development of a self-nanoemulsifying drug delivery system for telmisartan for oral drug delivery. Int. J. Pharm. Investig. 2011; 1: 112. DOI:10.4103/2230-973x.82431.

45. Huang, Y., Zhang, Q., Wang, J. R., Lin, K. L. and Mei, X. Amino acids as co-amorphous excipients for tackling the poor aqueous solubility of valsartan. Pharm. Dev. Technol. 2017; 22: 69–76. DOI:10.3109/10837450.2016.1163390.

46. Mahajan, A., Surti, N. and Koladiya, P. Solid dispersion adsorbate technique for improved dissolution and flow properties of lurasidone hydrochloride: characterization using 32 factorial design. Drug Dev. Ind. Pharm. 2018; 44: 463–471. DOI:10.1080/03639045.2017.1397687.

47. Davis, M. T., Potter, C. B. and Walker, G. M. Downstream processing of a ternary amorphous solid dispersion: The impacts of spray drying and hot melt extrusion on powder flow, compression and dissolution. Part. Technol. Forum 2018 - Core Program. Area. 2018; AIChE Annu. Meet. 2018; 117–138.

48. França, M. T., Nicolay, R. P., Klüppel Riekes, M., Munari Oliveira Pinto, J. and Stulzer, H. K. Investigation of novel supersaturating drug delivery systems of chlorthalidone: The use of polymer-surfactant complex as an effective carrier in solid dispersions. Eur. J. Pharm. Sci. 2018; 111: 142–152. DOI:10.1016/j.ejps.2017.09.043.

49. Alhayali, A., Tavellin, S. and Velaga, S. Dissolution and precipitation behavior of ternary solid dispersions of ezetimibe in biorelevant media. Drug Dev. Ind. Pharm. 2017; 43: 79–88 DOI:10.1080/03639045.2016.1220566.

50. Medarevic, D., Vranic, E., Potpara, Z. and Krstic, M. Development of ternary solid dispersions with hydrophilic polymer and surface adsorbent for improving dissolution rate of carbamazepine. 2018. doi:10.1016/j.jsps.2018.02.017.

51. Zhang, M. et al. Microcrystalline cellulose as an effective crystal growth inhibitor for the ternary Ibrutinib formulation. Carbohydr. Polym. 2020; 229: 115476. DOI:10.1016/j.carbpol.2019.115476.

52. Nguyen, D. N. and Van Den Mooter, G. The fate of ritonavir in the presence of darunavir. Int. J. Pharm. 2014; 475: 214–226. DOI:10.1016/j.ijpharm.2014.08.062.

53. Ruponen, M., Rusanen, H. and Laitinen, R. Dissolution and Permeability Properties of Co-Amorphous Formulations of Hydrochlorothiazide. J. Pharm. Sci. 2020; 109: 2252–2261. DOI:10.1016/j.xphs.2020.04.008.

54. Zhang, Y. et al. Combining co-amorphous-based spray drying with inert carriers to achieve improved bioavailability and excellent downstream manufacturability. Pharmaceutics. 2020; 12: 1–17. DOI:10.3390/pharmaceutics12111063.

55. Liu, J., Grohganz, H. and Rades, T. Influence of polymer addition on the amorphization, dissolution and physical stability of co-amorphous systems. Int. J. Pharm. 2020; 588: 119768. DOI:10.1016/j.ijpharm.2020.119768.

56. Pacułt, J. et al. Erratum: How can we improve the physical stability of co-amorphous system containing flutamide and bicalutamide? The case of ternary amorphous solid dispersions. (European Journal of Pharmaceutical Sciences. (2019) 136, (S0928098719302106), (10.1016/j.ejps. Eur. J. Pharm. Sci. 2021; 159: 1–9 DOI:10.1016/j.ejps.2020.105697.

57. Bunaciu, A. A., Udriştioiu, E. gabriela and Aboul-Enein, H. Y. X-Ray Diffraction: Instrumentation and Applications. Crit. Rev. Anal. Chem. 2015; 45: 289–299 DOI:10.1080/10408347.2014.949616.

58. Kilpeläinen, T. et al. Raman imaging of amorphous-amorphous phase separation in small molecule co-amorphous systems. Eur. J. Pharm. Biopharm. 2020; 155: 49–54. DOI:10.1016/j.ejpb.2020.08.007.

59. Haines, P. J., Reading, M. and Wilburn, F. W. Differential Thermal Analysis and Differential Scanning Calorimetry. 1998: 279–361. doi:10.1016/S1573-4374(98)80008-3 DOI:10.1016/S1573-4374(98)80008-3.

60. Dutta, A. Fourier Transform Infrared Spectroscopy. in Spectroscopic Methods for Nanomaterials Characterization. 2017; 2: 73–93 DOI:10.1016/B978-0-323-46140-5.00004-2.

Received on 15.01.2024 Revised on 11.05.2024

Accepted on 26.08.2024 Published on 20.01.2025

Available online from January 27, 2025

Research J. Pharmacy and Technology. 2025;18(1):409-414.

DOI: 10.52711/0974-360X.2025.00063

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.