Recent advances in pharmaceutical cocrystal design: leveraging in-silico technologies for enhanced drug development

Pharmaceutical Cocrystals: A Review on Design, Preparation, Application and Challenges.

Decision Science for Generic Drug Development and Review.

Pharmaceutical cocrystal is an emerging approach to tailor physicochemical and mechanical properties of drug substances. Cocrystals are composed of API and pharmaceutically acceptable coformer. It is used to address the solubility, dissolution, mechanical properties and stability of drugs. This review discusses introduction to cocrystal, preparation, and characterization, what USFDA says on cocrystal and role of Hansen solubility parameter to predict cocrystal. The effect of cocrystal on drug properties, dependence of cocrystal solubility on pH, concept of drug-drug cocrystal, and aerosil 200 as novel cocrystal former and impact of cocrystal on drug pharmacokinetic has also been presented in this review along with highly selected examples of cocrystals. Finally, how cocrystal offers an opportunity for patents is also delineated. Pharmaceutical cocrystals have ability to tailor physichochemical and mechanical properties of drug substances. It also provides opportunity for patentable invention. Therapeutic efficacy of drugs may be improved via drug-drug cocrystal. The pharmaceutical cocrystals are not fully explored and have potential for future development. Successful drug delivery can be achieved through cocrystallization. Pharmaceutical industry will be beneficial through successful cocrystallization of drug substances.

Editorial

Crossing Barriers From blood-to-brain and academia-to-industry

In this paper, a new pharmaceutical cocrystal was synthesized using apigenin (AP) and pharmaceutically acceptable conformer nicotinamide (Nico), and the drug delivery between AP-Nico pharmaceutical cocrystal and human serum albumin (HSA) in vivo was studied at atomic scale. The pharmaceutical cocrystal was characterized using Fourier-transform infrared (FTIR) spectroscopy, 1H NMR spectroscopy, differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD), and the self-assembling mechanism was explored. The dissolution and cumulative release in vitro were investigated. Molecular dynamic (MD) simulation combined with fluorescence spectroscopy was used to study the delivery mechanism of AP-Nico to HSA. The results showed that AP was pharmaceutically cocrystallized with Nico, which formed a pharmaceutical cocrystal mainly through hydrogen interaction between the -OH groups of AP and –NH2 groups of Nico. The solubility of the AP-Nico was 3 times higher than raw AP and the cumulative release rate was 71%. The fluorescence spectroscopy results showed that the AP-Nico pharmaceutical cocrystal bind with Sudlow’s site I inside the HSA molecule with hydrogen-bond interaction as the main force. The Sudlow’s site I of HSA conjugated with AP-Nico explains the conformational changes of HSA in-silico. This study provided a useful reference for synthesizing flavonoid pharmaceutical cocrystal to improve solubility and exploring the interaction mechanism while understanding its delivery mechanism in vivo.

Pharmaceutical cocrystals, owing to their manifold applications, are acting as bridge between drug discovery and pharmaceutical product development. The ability to scale up pharmaceutical cocrystals through continuous manufacturing approaches offers superior and economic pharmaceutical products. Moreover, cocrystals can be an aid for the nanoparticulate systems to solve the issues related to scale-up and cost. Cocrystals grabbed attention of academic researchers and pharmaceutical scientist due to their potential to target various diseases like cancer. The present review is mainly focussed on the diverse and comprehensive applications of pharmaceutical cocrystals in drug delivery including solubility and dissolution enhancement, improvement of bioavailability of drug, mechanical and flow properties of active pharmaceutical ingredients, controlled/sustained release and colour tuning of API. Besides, phytochemical based cocrystals, multi-drug cocrystals and cocrystals for tumour therapy have been discussed in this review. Additionally, recent progress pertinent to pharmaceutical cocrystals is also included, which may provide future directions to manufacturing and scale-up of cocrystals.

In the pharmaceutical industry, the strategic extension of drug exclusivity through polymorph patents presents a significant barrier to the timely market entry of generic competitors. This review delineates the use of pharmaceutical cocrystals as a sophisticated strategy to navigate these intellectual property hurdles. By forming a multi-component crystalline solid with a pharmaceutically acceptable co-former, a new solid form of the active pharmaceutical ingredient (API) is created, which is structurally and legally distinct from patented polymorphs. This approach provides a dual advantage: it offers a non-infringing pathway for generic development and simultaneously presents an opportunity to enhance the API's physicochemical properties. The formation of cocrystals can lead to significant improvements in solubility, dissolution rate, stability, and bioavailability, thereby creating value-added generic products with superior performance. This article examines the interplay between the Hatch-Waxman Act, regulatory pathways such as the ANDA, and the scientific principles of crystal engineering that underpin cocrystal design and synthesis. Through case studies of recently developed cocrystals for APIs like Daprodustat, Roxadustat, and Vadadustat, we illustrate the practical application and commercial potential of this strategy. Ultimately, pharmaceutical cocrystals represent a critical convergence of materials science, regulatory law, and drug delivery, offering an innovative and effective route for accelerating patient access to affordable and improved medicines.

Editorial

Solid-state mechanochemical grinding is important for promoting cocrystal formation, particularly in the design of new solids in the pharmaceutical industry. Pharmaceutical cocrystals are defined as crystalline materials comprising an active pharmaceutical ingredient (API) and one or more appropriate coformers in a definite stoichiometric ratio, formed via non-covalent interactions. Recently, both the US FDA (2013) and the EU EMA (2015) provided a Guidance for Industry and a Reflection Paper, respectively, emphasizing that cocrystals are a new type of substance with potential applications in the pharmaceutical industry. This paper contains a brief and systematic overview of pharmaceutical cocrystals prepared by four grinding processes: neat grinding, solvent-assisted grinding, thermal stress after neat grinding, and polymer-assisted grinding. The paper also highlights some examples of pharmaceutical cocrystals prepared by the above grinding approaches, and discusses the stability of cocrystals prepared by mechanical grinding. Also, an overview of cocrystals that are commercially available or undergoing clinical trials is given. A novel methodology for real-time and in situ monitoring of mechanochemical grinding reactions using various analytical techniques is addressed and can be expected to be applied in the near future.

The objective of this study was to improve the solubility of poorly water-soluble drugs by pharmaceutical cocrystal engineering techniques and select the best pharmaceutical forms with high solubility and solubilized formulations for progress from the early discovery stage toward the clinical stage. Several pharmaceutical cocrystals of TAK-020, a Bruton tyrosine kinase inhibitor, were newly discovered in the screening based on the solid grinding method and the slurry method, considering thermodynamic factors that dominate cocrystal formation. TAK-020/gentisic acid cocrystal (TAK-020/GA CC) was selected based on a physicochemical property of enhanced dissolution rate. TAK-020/GA CC was proven to be a reliable cocrystal formation with a definitive stoichiometric ratio by a variety of analytical techniques—pKa calculation, solid-state nuclear magnetic resonance, and single X-ray structure analysis from the view of regulation. Furthermore, its absorption was remarkable and beyond those achieved in currently existing solubilized formulation techniques, such as nanocrystal, amorphous solid dispersion, and lipid-based formulation, in dog pharmacokinetic studies. TAK-020/GA CC was the best drug form, which might lead to good pharmacological effects with regard to enhanced absorption and development by physicochemical characterization. Through the trials of solid-state optimization from early drug discovery to pharmaceutical drug development, the cocrystals can be an effective option for achieving solubilization applicable in the pharmaceutical industry.

Advances in artificial intelligence for drug delivery and development: A comprehensive review

The future of pharmaceuticals: Artificial intelligence in drug discovery and development

Solid dosage forms are by far the preferred drug delivery systems. However, these often face the problem of poor and erratic bioavailability during the drug development process. Numerous formulation strategies for drug delivery are currently under development, among which the solid forms such as polymorphs, solvates, salts, and cocrystals have been considered to be the most important for improving dissolution rate and bioavailability. Cocrystallization is a fairly new approach in pharmaceutical industry that can improve the solubility and, consequently, the bioactivity of the active pharmaceutical ingredient (API) without compromising its structural integrity. Pharmaceutical cocrystals have found their place in drug delivery, primarily due to their ability to produce alternative, viable solid forms when a more standard approach of salt and polymorph formation fails to deliver the desired objectives. Over the past few years, a number of papers have been published focusing on a broad range of subjects, from traditional crystal engineering to structure-property relationships of cocrystals. The present review, however, illustrates how the cocrystalline forms of APIs have improved their in vitro dissolution rate and in vivo bioavailability, often correlating well with their improved solubility as well.

A drug–drug cocrystal strategy to regulate stability and solubility: A case study of temozolomide/caffeic acid