INTRODUCTION:

A drug's solubility is one among the most crucial physicochemical characteristics that impacts its therapeutic effectiveness¹. The primary concern associated with the fabrication of novel chemical compounds and the production of generic drugs is poor solubility in water. In essence, a significant portion, exceeding 40% of newly developed pharmaceutical compounds are insoluble in water. Thus solubility presents one of the biggest challenge for the formulation scientists².

The most prevalent delivery system for drugs is by oral route. The dissolution rate is the key factor controlling the absorption process for drugs classified as class II (high membrane permeability, low aqueous solubility) by the Biopharmaceutical Classification System (BCS)³.

Reduced bioavailability can occur when an active drug substance has low solubility, hindering its dissolution and absorption. This often necessitates higher doses, which in turn increases the risk of adverse side effects. Enhancing the solubility of drugs with poor solublility, especially in oral formulations, is essential for improving dissolution and achieving more consistent absorption and bioavailability throughout the gastrointestinal tract⁴.

Numerous approaches have been explored to enhance rates of dissolution of drug, including: (a) Particles are made smaller to increase surface area. (b) utilizing water-soluble carriers to fabricate inclusion complexes (c) solubilisation of the substances by employing surfactant systems (d) developing prodrugs and derivatives of drug (e) altering the drug substances' solid state to enhance dissolution, such as by decreasing crystallinity using various techniques⁵.

The pharmaceutical industry generally favours the crystalline form of an API for delivery of drug because of its inherent thermodynamic stability. In recent years, crystal engineering of APIs has garnered significant interest among formulation experts.This approach is particularly effective in overcoming issues with poor water solubility, which helps create pharmaceutical products that are both stable and effective⁶. Recently, crystal engineering techniques have been extensively utilized to produce pharmaceutical co-crystals, significantly enhancing the physicochemical properties of active pharmaceutical ingredients (APIs)⁷.

1.1 PHARMACEUTICAL COCRYSTALS:

Co-crystals: The USFDA defines cocrystals as“crystalline materials formed by combining an active pharmaceutical ingredient with another molecule in a specific ratio within a single crystal lattice, held together by non-ionic and non-covalent bonds”. The main interactions that lead to the formation of cocrystals are non-covalent ones, like hydrogen bonds (the primary interaction), halogen bonding, π-π interactions, and van der Waals forces.

Co-former: As per USFDA co-former can be defined as "a component that interacts non-ionically with the active pharmaceutical ingredient in the crystal lattice, that is not a solvent (including water), and is typically non-volatile".Coformers are typically water-soluble molecules, such as caffeine, nicotinamide, saccharin, and carboxylic acids⁸_.

1.1.1 Advantages of Cocrystals^9,10

· Cocrystals modify drug properties but the molecule's inherent pharmacological activity remains unaffected.

· Cocrystals can be formed with various types of molecules, encompassing both non-ionizable and weakly ionizable APIs. This offers advantages over salt formation, which is limited to acidic or basic counter-ions.

· Cocrystals, being crystalline, are generally more stable than amorphous solid dispersions, which may exhibit physicochemical stability issues.

· Salt formation is often limited to acidic or basic counter-ions due to toxicological concerns. In contrast, cocrystal screening allows for a broader selection of potential coformers, which are not restricted by toxicological limitations

1.1.2 Development of Cocrystals – Various Strategies^11,12,13

A. Solution Based Cocrystallization:

These method involve three phases—the API, coformer, and solvent.The ideal condition for co-crystallization is when the API and coformer should be either saturated or unsaturated, while the cocrystal itself should be supersaturated. Under experimental conditions, the level of supersaturation of the co-crystal plays a crucial role in the co-crystallization process and can be regulated by varying the API and conformer concentration.

· Solvent Evaporation: In this method, constituent parts of cocrystal are fully solubilized in an appropriate solvent at the correct stoichiometric ratio, followed by evaporation of solvent to yield the co-crystal. This method involves three essential steps for creating cocrystals :supersaturation, nucleation, and crystal growth.The supersaturation phase acts as the rate-limiting step for both nucleation and crystal growth.This method produces cocrystals of excellent quality and purity on a small scale without the use of sophisticated equipment.

· Anti-solvent cocrystallization:Here, supersaturation of the API and coformer medium is achieved by adding an organic solvent or buffer, in which the drug is insoluble (antisovent),but should be miscible with the solvent, leading to the precipitation of the cocrystal ^11,13. It is an efficient strategy to regulate the particle size, quality and cocrystals properties

· Cooling crystallization: Here, the solution is initially heated and then letting to stabilize for a period of time. Once stabilization is achieved, cooling begins at an appropriate rate of temperature decrease (°C/min) to promote the formation of a co-crystal within the solution. The crystallized product is subsequently collected through vacuum filtration. The heating temperature is dependent on the specific solvent and co-crystal component used^.

· Slurry method: This method utilizes only a small amount of solvent. The API and coformer are thoroughly mixed with the solvent, and the cocrystallization process proceeds as the slurry solution is stirred. The cocrystals are then obtained by subjecting the solvent for evaporation at room temperature.

B. Solid Based Cocrystallization:

This is a highly efficient and eco-friendly approach, requiring minimal or no solvent. Co-crystals form naturally through grinding or direct contact with higher power inputs. This method offers a viable alternative to solution-based co-crystallization techniques, which can pose environmental risks due to solvent use.

· Contact co-crystallization: Following a gentle blending of the raw ingredients, a natural interaction between the drug and coformers may take place. Proposed mechanisms for spontaneous crystallization through contact include the formation of a eutectic phase, amorphization, moisture absorption, vapor diffusion between the two solids, and long-range anisotropic molecular movement. Factors such as smaller particle sizes, increased temperatures, and higher humidity levels can enhance the development of cocrystals_.

· Grinding: The Grinding method is classified into two types:

a) Solid-state grinding.

b) Solvent drop grinding (liquid assisted grinding)

a. Solid State Grinding: The API and coformer are mixed in the suitable stoichiometric ratios and then compressed and ground together by a mortar and pestle, vibration mill or ball mill. Typically, the grinding process takes between 30 and 60 minutes.

b. Liquid-Assisted Grinding (Solvent Drop Grinding): A new twist of the traditional grinding method, which involves grinding the two components (API & coformer) and introducing a minimal quantity of solvent during the milling process. This approach significantly accelerates the co-crystallization reaction. Here, the molecular diffusion, which is crucial for forming a multicomponent framework is enhanced by the solvent. Additionally, it serves as a catalyst to raise the the crystal system’s supramolecular selectivity.

· Melting crystallization: In this method, vigorous mixing and heating of the drug and coformers are employed to produce cocrystals, improving surface interactions without the use of a solvent.

Table 1 : Some reported pharmaceutical cocrystals

Sl. No.	Author	Drug	Method of preparation	Ref.
1	Mehta CH et al	Aceclofenac	Solvent evaporation, dry grinding	14
2	Bose et al	Glimeperide	Slow evaporation	15
3	Jassim ZE et al	Dextromethorphan HBr	Co-grinding, solvent evaporation & liquid assisted grinding method	16
4	Ahirrao SP et al	Etodolac	Cooling cocrystallization	17
5	Thomas JE et al	Valsartan	Solvent evporation	18
6	Batool F et al	Glipizide	Dry grinding, slurry, liquid-assisted grinding, and solvent evaporation	19
7	Utami DW et al	Mefenamic acid	Melt crystallization	20
8	Machado TC et al	Meloxicam	Reaction crystallization	21
9	Nikam VJ et al	Nebivolol hydrochloride	Liquid assisted grinding and solvent evaporation	22
10	Ashish V. Ther et al	Clinidipine	solid-state grinding and solvent evaporation method	23
11	Albadri AA et al	Tenoxicam	Solvent evaporation and grinding method	24
12	Alatas et al	Telmisartan	Solvent drop grinding and solvent evaporation	25
13	Budiman A et al	Glibenclamide	Solvent evaporation	26

1.3 NANO – COCRYSTALS:

Nano-cocrystals refer to crystals within the nanometer scale, offering enhanced drug solubility compared to conventional cocrystals³⁶. Unlike nanocrystals, which consist of a single molecule, nanococrystals combine two or more different molecular species within a single nanocrystal. As a result, nanococrystals offer several advantages over traditional nanocrystals, as the newly formed nanococrystal can inherit or develop unique properties³⁷.

Nano-cocrystals, the hybrid of nanocrystal and cocrystal technologies has been shown to enhance various properties, including thermo-sensitivity, photochemical stability, dissolution rates, mechanical behavior, and reduce the side effects of active pharmaceutical ingredients (APIs). This improvement results from the combined advantages of both cocrystals and nanocrystals³⁸.

Incase of nanococrystals, the solubility can be altered through two mechanisms: reducing surface area phenomena in nanocrystals or utilizing the spring-parachute effect in cocrystals. In nanocrystals, maintaining a supersaturated state over an extended period can be challenging due to the trace amounts of stabilizers present. However, when the spring-parachute effect of cocrystals is integrated into nanococrystals, it becomes easier to sustain supersaturation compared to using nanocrystals alone.

1.3.1 Development of Nano-cocrystals^36-39

A. Top-down approach:

· High-pressure homogenization (HPH): It is a valuable technique for creating nanosized crystals, particularly relevant for boosting the rate of ability to dissolve and bioavailability of pharmaceuticals. Studies have demonstrated the successful production of nano-cocrystals using HPH, such as those involving baicalein with poloxamer 188 as a stabilizer and praziquantel with a combination of poloxamer 188 and other polymers.While effective, the widespread application of HPH for nano-crystal production faces certain challenges. including high energy consumption, lengthy processing times, and limitations in achieving consistent and uniform particle sizes.

· Milling:

i. Solid state milling: It is a solvent-free technique for preparing cocrystals by mechanically grinding solid components together. This method involves mixing the desired materials in the correct proportions and then subjecting them to grinding using tools like mortars and pestles, ball mills, or vibration mills. Typically, this process takes between 30 and 60 minutes. It effectively reduces particle size, increasing the specific surface area. Compared to solution-based methods, it often exhibits higher selectivity in cocrystal formation. Additionally, it is relatively simple to operate and allows for rapid cocrystal production.One major drawback is the tendency for particles to agglomerate into larger, micron-sized particles, which can hinder desired properties.

ii. Liquid assisted milling: It entails incorporating a tiny quantity of solvent into the grinding procedure.This addition of solvent can significantly influence the resulting crystal form, potentially favoring specific polymorphs. This method offers several advantages, including enhanced crystallization rates by accelerating the formation of crystals, particularly for materials that crystallize slowly under conventional dry grinding; Improved product performance;Polymorph control by carefully selecting the solvent, it is possible to control the specific crystal form that is obtained.However, this method also has some limitations including scalability challenges,high energy consumption and it may not always yield products with the highest possible purity.

B. Bottom –up approach:

· Anti-solvent precipitation: It is a widely used technique for preparing nano-cocrystals, particularly when dealing with systems containing both soluble and insoluble components. The differing solubilities of these components in aqueous media often pose significant challenges in achieving stable nano-cocrystal formation .To overcome these challenges, a common approach involves utilizing an anti-solvent system in conjunction with stabilizers. The principle behind this method relies on the contrasting solubilities of the cocrystal components in the solvent and the anti-solvent.The cocrystal components' solubility is drastically reduced when the anti-solvent is added to the system, which causes them to precipitate quickly.The successful application of anti-solvent precipitation in the medical field hinges on the judicious selection of the anti-solvent. However, a lack of systematic studies in this area has limited the widespread use of this technique.

1.3.2 Characterization of Nano Cocrystals³⁹

Table 4: Characterization techniques of nanococrystals

Characterization technique

Analysis object

DSC (Differential scanning caloorimetry)

TGA (Thermogravimetric analysis)

FTIR spectroscopy

Raman spectroscopy

SEM, TEM,AFM

Determines crystal structure, polymorphism, and amorphous content.

Measures enthalpy changes associated with phase transitions (e.g., melting, glass transition).

Quantifies mass loss due to decomposition or volatilization.

Identifies functional groups and molecular structure.

Provides information about molecular vibrations and structure.

Visualizes particle morphology and size.

Table 5: Some reported nanococrystals

Sl. No.	Authors	Drug	Preparation method	Ref.
1	Witika BA et al	Lamivudine+ Zidovudine	Wet media milling (Top down approach)	40
2	Bhandari et al	Ezetimibe	Antisolvent precipitation	41
3	Hidayat AF et al	Mefenamic acid	Solvent evaporation followed by sonochemical technique	42
4	De Smet L et al	Itraconazole	Wet milling	43
5	Huang Y et al	Phenazopyridine HCl	Sonochemical approach	44
6	Nugrahani I et al	Diclofenac-proline	Fast evaporation assisted by the microwaving method.	45
7	Salem A et al	Sulfamethazine	High-pressure homogenization (HPH)	46
8	Karashima M et al	Carbamazepine, Indomethacin	Wet milling	47
9	Jiaxin Pi et al	Bicalein	High pressure homogenization	48

CONCLUSION:

Nanococrystal technology has emerged as a transformative approach in pharmaceutical science, addressing critical limitations associated with poorly water-soluble drugs. By integrating nanoscale particle size reduction and coformer selection through crystal engineering, this method significantly improves drug solubility, dissolution rate, and bioavailability. Its ability to enhance wettability, stability, and scalability makes it a promising solution for modern drug development challenges. Despite the significant progress and numerous advantages, further research is essential to tackle issues such as process optimization, cost-effectiveness, and regulatory compliance. The integration of advanced characterization techniques and innovative preparation methods will be key to unlocking its full potential. As this field continues to evolve, nanococrystal technology offers exciting opportunities to revolutionize drug delivery, making life-saving medications more efficient and accessible to patients worldwide.

REFERENCES:

1. Ammanage, A.; Rodriques, P.; Kempwade, A.; Hiremath, R. Formulation and Evaluation of Buccal Films of Piroxicam Co-Crystals. Future J. Pharm. Sci. 2020; 6(1). https://doi.org/10.1186/s43094-020-00033-1

2. Savjani, K. T.; Gajjar, A. K.; Savjani, J. K. Drug Solubility: Importance and Enhancement Techniques. ISRN Pharm. 2012; 2012, 1–10. https://doi.org/10.5402/2012/195727

3. Ibrahim, M. M.; El-Nabarawi, M.; El-Setouhy, D. A.; Fadlalla, M. A. Polymeric Surfactant-Based Etodolac Chewable Tablets: Formulation and In Vivo Evaluation. AAPS PharmSciTech. 2010; 11(4): 1730–1737. https://doi.org/10.1208/s12249-010-9548-z

4. Malviya, V.; Burange, P.; Thakur, Y.; Tawar, M. Enhancement of Solubility and Dissolution Rate of Atazanavir Sulfate by Nanocrystallization. Indian J. Pharm. Educ. Res. 2021, 55(3s), S672–S680. https://doi.org/10.5530/ijper.55.3s.174

5. Shewale, S.; Shete, A. S.; Doijad, R. C.; Kadam, S. S.; Patil, V. A.; Yadav, A. V. Formulation and Solid State Characterization of Nicotinamide-Based Co-Crystals of Fenofibrate. Indian J. Pharm. Sci. 2015, 77(3), 328. https://doi.org/10.4103/0250-474x.159669

6. Blagden, N.; De Matas, M.; Gavan, P. T.; York, P. Crystal Engineering of Active Pharmaceutical Ingredients to Improve Solubility and Dissolution Rates. Adv. Drug Deliv. Rev. 2007; 59(7): 617–630. https://doi.org/10.1016/j.addr.2007.05.011

7. Gurav, A. S.; Kulkarni, A. S. Efavirenz Cocrystals with Ascorbic Acid: A Strategy for Polymorphic Modification and Improvement of Dissolution Properties. Res. J. Pharm. Technol. 2024; 17: 213–221. https://doi.org/10.52711/0974-360x.2024.00034

8. Emami, S.; Siahi-Shadbad, M.; Adibkia, K.; Barzegar-Jalali, M. Recent Advances in Improving Oral Drug Bioavailability by Cocrystals. Bioimpacts. 2018; 8(4): 305–320. https://doi.org/10.15171/bi.2018.33

9. Buddhadev, S. S.; Garala, K. C. Pharmaceutical Cocrystals—A Review. Proceedings. 2021; 69(1): 14. https://doi.org/10.3390/proceedings2020062014

10. Yadav, S.; Agnihotri, J.; Parab, I. Co-Crystal: An Overview on the Novel Techniques for the Formation of CoCrystal and Its Potential Benefit in the Pharmaceutical Industry. Int. J. Pharm. Pharm. Res. 2022; 23(4): 345–370.

11. Jit, T.; Shil, D.; Dasgupta, R. K.; Mallick, S.; Mukherjee, S. Cocrystal: A Review on the Design and Preparation of Pharmaceutical Cocrystals. Asian J. Res. Pharm. Sci. 2023; 13(4): 296–302. https://doi.org/10.52711/2231-5659.2023.00050

12. Kumar, M. D. T.; Shree, D. M. A Review on Role of Cocrystals in Formulation Development of Insoluble Drugs. World J. Pharm. Res. 2023, 12, 546–565. https://www.wjpr.net

13. Samineni, R.; Chimakurthy, J.; Sumalatha, K.; Dharani, G.; Rachana, J.; Manasa, K., et al. Co-Crystals: A Review of Recent Trends in Co-Crystallization of BCS Class II Drugs. Res. J. Pharm. Technol. 2019; 12(7): 3117. https://doi.org/10.5958/0974-360x.2019.00527.4

14. Mehta, C. H.; Srinivas, P. P.; Sb, A.; Mahany, K. B. F.; Koteshwara, K.; Nayak, U. Y. Computational and Experimental Insights in Design and Development of Aceclofenac Co-Crystals. Res. J. Pharm. Technol. 2022; 15(8): 3709–3716. https://doi.org/10.52711/0974-360x.2022.00622

15. Bose, P.; Chandra, S.; Das, A.; Roy, T.; Paul, S.; Mukherjee, L. Enhancement of Solubility of an Oral Hypoglycaemic Drug, Glimepiride by the Technique Cocrystallisation. Int. J. Pharm. Sci. Res. 2021; 12(2): 1092–1098. https://doi.org/10.13040/ijpsr.0975-8232.12(2).1092-08

16. Jassim, Z. E.; Al-Kinani, K. K.; Alwan, Z. S. Preparation and Evaluation of Pharmaceutical Cocrystals for Solubility Enhancement of Dextromethorphan HBr. Int. J. Drug Deliv. Technol. 2021: 11(4).

17. Ahirrao, S. P.; Sonawane, M. P.; Bhambere, D. S.; Udavant, P. B.; Ahire, E. D.; Kanade, R., et al. Cocrystal Formulation: A Novel Approach to Enhance Solubility and Dissolution of Etodolac. Biosci. Biotechnol. Res. Asia 2022; 19(1): 111–119. https://doi.org/10.13005/bbra/2971

18. Thomas, J. E.; Nayak, U. Y.; Jagadish, P.; Koteshwara, K. Design and Characterization of Valsartan Co-Crystals to Improve Its Aqueous Solubility and Dissolution Behavior. Res. J. Pharm. Technol. 2017; 10(1): 26. https://doi.org/10.5958/0974-360x.2017.00007.5

19. Batool, F.; Ahmad, M.; Minhas, M.; Khalid, Q.; Idrees, H.; Khan, F. Use of Glutaric Acid to Improve the Solubility and Dissolution Profile of Glipizide through Pharmaceutical Cocrystallization. Acta Pol. Pharm. Drug Res. 2019; 76(1): 103–114. https://doi.org/10.32383/appdr/94246

20. Utami, D.; Nugrahani, I.; Ibrahim, S. Studies of Preparation, Characterization, and Solubility of Mefenamic Acid-Nicotinamide Co-Crystal Synthesized by Using Melt Crystallization Method. Asian J. Pharm. Clin. Res. 2017; 10(5): 135. https://doi.org/10.22159/ajpcr.2017.v10i5.15863

21. Machado, T. C.; Gelain, A. B.; Rosa, J.; Cardoso, S. G.; Caon, T. Cocrystallization as a Novel Approach to Enhance the Transdermal Administration of Meloxicam. Eur. J. Pharm. Sci. 2018; 123: 184–190. https://doi.org/10.1016/j.ejps.2018.07.038

22. Nikam, V. J.; Patil, S. B. Pharmaceutical Cocrystals of Nebivolol Hydrochloride with Enhanced Solubility. J. Cryst. Growth. 2020, 534, 125488. https://doi.org/10.1016/j.jcrysgro.2020.125488

23. Ther, A. V.; Bhongade, Y. M.; Sawkare, A. D. Pharmaceutical Cocrystal of Cilnidipine–Benzoic Acid (Design, Formulation, and Evaluation). Int. J. Pharm. Pharm. Res. 2020; 19(1): 739–754. https://www.ijppr.humanjournals.com

24. Albadri, A. A.; Jihad, M. I.; Radhi, Z. A. Preparation, Characterization, and In Vitro Evaluation of Tenoxicam–Paracetamol Cocrystal. Int. J. Drug Deliv. Technol. 2020; 10(4): 542–546.

25. Alatas, F.; Ratih, H.; Soewandhi, S. N. Enhancement of Solubility and Dissolution Rate of Telmisartan by Telmisartan–Oxalic Acid Co-Crystal Formation. Int. J. Pharm. Pharm. Sci. 2015; 7(3): 423–426.

26. Budiman, A.; Apriliani, A.; Qoriah, T.; Megantara, S. Glibenclamide–Nicotinamide Cocrystals Synthesized by the Solvent Evaporation Method to Enhance Solubility and Dissolution Rate of Glibenclamide. Int. J. Drug Deliv. Technol. 2019; 9(1): 21–26. https://doi.org/10.25258/ijddt.9.1.4

27. Narwade, S.; Bagad, D. Nanocrystals—Universal Approach for Poorly Hydrophilic Drug. Res. J. Pharm. Dosage Forms Technol. 2013; 5(5): 245–251.

28. Patel, S. R.; Shah, D. P. A Review on Nanocrystals Drug Delivery System. Res. J. Pharm. Technol. 2015; 8(5): 647. https://doi.org/10.5958/0974-360x.2015.00103.1

29. Xalxo, N.; Naha, A.; Dhoot, A.; Priya, J. Nanocrystals: A Newer Technological Advancement in Drug Delivery. Res. J. Pharm. Technol. 2018; 11(4): 1685. https://doi.org/10.5958/0974-360x.2018.00314.1

30. Gaikwad, N. A.; Pujari, A. S.; Mane, I. V.; Vambhurkar, G. B.; Honmane, P. P. Formulation and Characterization of Atorvastatin Nanocrystal Tablet. Asian J. Pharm. Technol. 2019; 9(2): 99. https://doi.org/10.5958/2231-5713.2019.00017.5

31. Malviya, V.; Burange, P.; Thakur, Y.; Tawar, M. Enhancement of Solubility and Dissolution Rate of Atazanavir Sulfate by Nanocrystallization. Indian J. Pharm. Educ. Res. 2021; 55(3s): S672–S680. https://doi.org/10.5530/ijper.55.3s.174

32. Vadhera, B.; Shah, S.; Dudhat, K.; Dhaval, D.; Singe, S.; Prajapati, B. G. Ketoconazole Nanocrystals Fortified Gel for Improved Transdermal Applications. Nanofabrication. 2024, 9.

33. Ochi, M.; Kawachi, T.; Toita, E.; Hashimoto, I.; Yuminoki, K.; Onoue, S., et al. Development of Nanocrystal Formulation of Meloxicam with Improved Dissolution and Pharmacokinetic Behaviors. Int. J. Pharm. 2014; 474(1–2): 151–156. https://doi.org/10.1016/j.ijpharm.2014.08.022

34. Sharma, A.; Jain, A. P.; Arora, S. Formulation and In Vitro Evaluation of Nanocrystal Formulation of Poorly Soluble Drugs. J. Drug Deliv. Ther. 2020, 9(4-s), 1183–1190. https://doi.org/10.22270/jddt.v9i4-s.3873

35. Özdemir, S.; Üner, B.; Karaküçük, A.; Çelik, B.; Sümer, E.; Taş, Ç. Nanoemulsions as a Promising Carrier for Topical Delivery of Etodolac: Formulation Development and Characterization. Pharmaceutics. 2023, 15(10), 2510. https://doi.org/10.3390/pharmaceutics15102510

36. More, A.; Bade, P.; Darekar, S. A Review of Pharmaceutical Nano-Cocrystal: A Novel Strategy to Improve the Chemical and Physical Properties for Poorly Water Soluble Drugs. J. Adv. Sci. Res. 2023, 14(2), 40–43. https://doi.org/10.55218/jasr.202314203

37. Liu, M.; Hong, C.; Li, G.; Ma, P.; Xie, Y. The Generation of Myricetin–Nicotinamide Nanococrystals by Top-Down and Bottom-Up Technologies. Nanotechnology. 2016, 27(39), 395601. https://doi.org/10.1088/0957-4484/27/39/395601

38. Thakor, P.; Yadav, B.; Modani, S.; Shastri, N. R. Preparation and Optimization of Nano-Sized Cocrystals Using a Quality by Design Approach. CrystEngComm. 2020, 22(13), 2304–2314. https://doi.org/10.1039/c9ce01930h

39. Tan, J.; Liu, J.; Ran, L. A Review of Pharmaceutical Nano-Cocrystals: A Novel Strategy to Improve the Chemical and Physical Properties for Poorly Soluble Drugs. Crystals. 2021; 11(5), 463. https://doi.org/10.3390/cryst11050463

40. Witika, B. A.; Smith, V. J.; Walker, R. B. Top-Down Synthesis of a Lamivudine–Zidovudine Nano Co-Crystal. Crystals. 2020, 11(1), 33. https://doi.org/10.3390/cryst11010033

41. Bhandari, J.; Kanswami, N.; Pk, L. L. Nano Co-Crystal Engineering Technique to Enhance the Solubility of Ezetimibe. J. Young Pharm. 2020, 12(2s), s10–s15. https://doi.org/10.5530/jyp.2020.12s.40

42. Hidayat, A. F.; Sofiyandini, L.; Darusman, F. Development and Characterization of Mefenamic Acid–Nicotinamide Nano-Cocrystal. Heliyon. 2023. https://doi.org/10.2139/ssrn.4556716

43. De Smet, L.; Saerens, L.; De Beer, T.; Carleer, R.; Adriaensens, P.; Van Bocxlaer, J., et al. Formulation of Itraconazole Nanococrystals and Evaluation of Their Bioavailability in Dogs. Eur. J. Pharm. Biopharm. 2014, 87(1), 107–113. https://doi.org/10.1016/j.ejpb.2013.12.016

44. Huang, Y.; Li, J. M.; Lai, Z. H.; Wu, J.; Lu, T. B.; Chen, J. M. Phenazopyridine–Phthalimide Nano-Cocrystal: Release Rate and Oral Bioavailability Enhancement. Eur. J. Pharm. Sci. 2017, 109, 581–586. https://doi.org/10.1016/j.ejps.2017.09.020

45. Nugrahani, I.; Auli, W. N. Diclofenac–Proline Nano-Co-Crystal Development, Characterization, In Vitro Dissolution and Diffusion Study. Heliyon. 2020, 6(9), e04864. https://doi.org/10.1016/j.heliyon.2020.e04864

46. Salem, A.; Takácsi-Nagy, A.; Nagy, S.; Hagymási, A.; Gősi, F.; Vörös-Horváth, B., et al. Synthesis and Characterization of Nano-Sized 4-Aminosalicylic Acid–Sulfamethazine Cocrystals. Pharmaceutics. 2021, 13(2), 277. https://doi.org/10.3390/pharmaceutics13020277

47. Karashima, M.; Kimoto, K.; Yamamoto, K.; Kojima, T.; Ikeda, Y. A Novel Solubilization Technique for Poorly Soluble Drugs through the Integration of Nanocrystal and Cocrystal Technologies. Eur. J. Pharm. Biopharm. 2016, 107, 142–150. https://doi.org/10.1016/j.ejpb.2016.07.006

48. Pi, J.; Wang, S.; Li, W.; Kebebe, D.; Zhang, Y.; Zhang, B., et al. A Nano-Cocrystal Strategy to Improve the Dissolution Rate and Oral Bioavailability of Baicalein. Asian J. Pharm. Sci. 2019; 14(2): 154–164. https://doi.org/10.1016/j.ajps.2018.04.009

Received on 18.02.2025 Revised on 17.06.2025

Accepted on 01.08.2025 Published on 03.04.2026

Available online from April 06, 2026

Research J. Pharmacy and Technology. 2026;19(4):1928-1934.

DOI: 10.52711/0974-360X.2026.00277

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

Sl. No.	Author	Drug	Preparation method	Ref
1	Malviya et al	Atazanavir sulphate	Solvent-Antisolvent (Precipitation) Method	31
2	Bhavin Vadher et al	Ketoconazole	Top-down media milling technique	32
3	M. Ochi et al	Meloxicam	Wet-milling	33
4	Sharma et al	Rosuvastatin	Solvent-Antisolvent (Precipitation) Method	34
5	Ozdemir S et al	Etodolac	High shear homogenization and ultrasonication methods	35