Enhancing the stability of active pharmaceutical ingredients by the cocrystal strategy

Cocrystals consist of two molecules bonded together in a single crystal lattice giving rise to wide applications including improving solubility of poorly soluble pharmaceuticals. Cocrystallization reaction occurs in the oily phase of liquid−liquid phase separation (LLPS) after it is mixed with coformers. Indomethacin− saccharin cocrystal formation was monitored in situ, and the kinetics of crystallization were determined. The crystallization rates show that the process can be proposed to prevent unwanted oily phase formation during LLPS.

Section: Resultsmentioning

confidence: 99%

Interfacial Cocrystallization Using Oily Phase via Liquid–Liquid Phase Separation

Al-Hanafi

Alsirawan

Seaton

et al. 2022

“…As an alternative method, cocrystal formation is one of the novel techniques to modify physicochemical properties. The benefit of cocrystal formation in comparison with salt are that it does need to have ionizable functional groups …”

Section: Introductionmentioning

confidence: 99%

“…The benefit of cocrystal formation in comparison with salt are that it does need to have ionizable functional groups. 7 There are some advantages for cocrystals over the salt formation method: (1) the cocrystal method is suitable for drugs with nonionizable groups, (2) also cocrystal formation of drugs with a highly functionalized groups is more straightforward than salt formation methods, (3) chiral drugs may undergo racemization during salt formation. 8 The United States Food and Drug Administration (FDA), in its recently published guideline, pointed out this subject; i.e., if pK a base − pK a acid ≥ 1, proton transfer is significant enough for salt formation; on the contrary, if ΔpK a < 1, proton transfer is not possible, which leads to cocrystal formation.…”

Section: Introductionmentioning

confidence: 99%

Solution Stability of Pharmaceutical Cocrystals

Alvani

Shayanfar

2022

In recent years, pharmaceutical cocrystals as a new solid form have received considerable attention among the applied novel methods for modifying drug substance characteristics. Crystal engineering offers an excellent opportunity to improve physicochemical and pharmacokinetic properties such as solubility, dissolution rate, permeability, bioavailability, biochemical/physical stability, etc. Application of the cocrystal form in the pharmaceutical industry and in academia is becoming a popular method to overcome solubility disadvantages of the active pharmaceutical ingredient (API). Due to manipulation of the API crystalline structure by cocrystal formation, solubility is not the only affected property; some other properties of the newly produced solid form must be considered to fulfill the desired therapeutic efficacy. The stability of the cocrystal in solution is one of these influential features. Regarding the aqueous nature of the gastrointestinal tract, unwanted solution-mediated phase transformation of a cocrystal to a more stable form causes inefficient drug delivery. It may potentially reduce the drug concentration in the circulation. Cocrystal transformation products could be a different polymorph, hydrated form, or mixture of the API and coformer. This review focuses on the solution stability of cocrystals and the effects of various factors such as polymers, surfactants, biorelevant media, organic solvents, and pH.

“…In order to improve the API's physicochemical properties without impairing its pharmaceutical properties, the API can be crystallized with another molecule called "coformer". This approach is referred to as "cocrystallization" and has been given special attention from pharmaceutical industries during these last years 27 . The coformers are usually chosen for their innocuousness in the GRAS list (« Generally Recognized As Safe » molecules), the coformer can also be another API.…”

Section: Introductionmentioning

confidence: 99%

“…This approach is referred to as "cocrystallization" and has been given special attention from pharmaceutical industries during these last years. 27 The coformers are usually chosen for their innocuousness in the GRAS list ("generally recognized as safe" molecules), and the coformer can also be another API. Cocrystals present different physicochemical properties than the pure API: solubility in water may be increased, stability can be enhanced, susceptibility to moisture can be reduced, and so forth.…”

Section: ■ Introductionmentioning

confidence: 99%

New Cocrystallization Method: Non-photochemical Laser-Induced Nucleation of a Cocrystal of Caffeine–Gallic Acid in Water

Mellah

Nicolaı̈

Fournier

et al. 2022

This paper reports for the first time the crystallization of cocrystals (caffeine -gallic acid) in water using the Non-Photochemical Laser-Induced Nucleation (NPLIN) technique. The nucleation temporal control of NPLIN and the induction time reduction (70 times shorter than spontaneous nucleation) allow the obtention of cocrystals on-demand, with excellent repeatability. Prior to NPLIN experiments, solubility measurements, metastable zone limit determination, and spontaneous nucleation (SN) are carried out. Supersaturated solutions at three different molarities of caffeine (0.0158, 0.0167 and 0.0179 M) are prepared and dissolved at 338 K. Supersaturated solutions are exposed to a 532 nm wavelength nanosecond pulsed laser at 296 K. Some hours later crystals can be filtered. The impact of supersaturation on probability of nucleation has been studied and the result shows a higher supersaturation implies a higher probability of nucleation. Crystalline form characterization has employed a combination of Raman scattering, high-performance liquid chromatography, thermogravimetry, differential scanning calorimetry, and powder X-ray diffraction; the sizes of the cocrystals being too small for a single-crystal X-ray diffraction experiment. Two different cocrystal forms are obtained: a new polymorph of hemihydrate CAFGAL.0.5H2O from spontaneous nucleation by precipitation, and a new hydrate form CAFGAL.1.5H2O from NPLIN and from spontaneous nucleation of a supersaturated solution without evaporation. These results open a promising way to crystallize cocrystals in the context of the pharmaceutical industry.