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The objective of this work was to develop a better understanding of a potentially scalable, liquid antisolvent (LAS) precipitation process, for the preparation of stable aqueous suspensions of ultrafine particles of poorly watersoluble active pharmaceutical ingredients (APIs). A novel combination of jets, ultrasound, polymers, and surfactants was used for the precipitation and stabilization of ultrafine particles of griseofulvin (GF). Use of ultrasound and high stream velocities enhances micromixing, whereas addition of polymers/surfactants inhibits/lowers the particle growth. A combination of ultrasound, high jet velocities, and stabilizers decreased the GF particle size to 1.04 µm ((0.46 µm) from 30.8 µm ((14.2 µm), when none of the treatments were used. A rational understanding was developed for predicting process performance and selecting suitable particle growth inhibitors/stabilizers. Favorable process conditions and combinations of polymer and surfactants were also identified experimentally for the precipitation of ultrafine particles of GF with a narrow particle size distribution (PSD).

Biopharmaceutics Classification System (BCS) Class II and IV drugs suffer from poor aqueous solubility and hence low bioavailability. Most of these drugs are hydrophobic and cannot be developed into a pharmaceutical formulation due to their poor aqueous solubility. One of the ways to enhance the aqueous solubility of poorlywater-soluble drugs is to use the principles of crystal engineering to formulate cocrystals of these molecules with water-soluble molecules (which are generally called coformers). Many researchers have shown that the cocrystals significantly enhance the aqueous solubility of poorly water-soluble drugs. In this review, we present a consolidated account of reports available in the literature related to the cocrystallization of poorly water-soluble drugs. The current practice to formulate new drug cocrystals with enhanced solubility involves a lot of empiricism. Therefore, in this work, attempts have been made to understand a general framework involved in successful (and unsuccessful) cocrystallization events which can yield different solid forms such as cocrystals, cocrystal polymorphs, cocrystal hydrates/solvates, salts, coamorphous solids, eutectics and solid solutions. The rationale behind screening suitable coformers for cocrystallization has been explained based on the rules of five i.e., hydrogen bonding, halogen bonding (and in general non-covalent bonding), length of carbon chain, molecular recognition points and coformer aqueous solubility. Different techniques to screen coformers for effective cocrystallization and methods to synthesize cocrystals have been discussed. Recent advances in technologies for continuous and solvent-free production of cocrystals have also been discussed. Furthermore, mechanisms involved in solubilization of these solid forms and the parameters influencing dissolution and stability of specific solid forms have been discussed. Overall, this review provides a consolidated account of the rationale for design of cocrystals, past efforts, recent developments and future perspectives for cocrystallization research which will be extremely useful for researchers working in pharmaceutical formulation development.

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Curcumin is a pharmaceutically viable ingredient derived from the rhizome of the Indian spice turmeric (Curcuma longa). However, curcumin suffers from poor water solubility, which limits its bioavailability. In this work, we report studies carried out to investigate cocrystallization of curcumin to improve its aqueous solubility. Salicylic acid and hydroxyquinol were used as coformers. Binary phase diagrams were constructed for curcumin−salicylic acid and curcumin− hydroxyquinol systems using differential scanning calorimetric (DSC) thermograms obtained for mixtures prepared by solidstate grinding. The curcumin−salicylic acid system was found to form an eutectic at a curcumin mole fraction of 0.33, whereas the curcumin−hydroxyquinol system clearly exhibited a cocrystal forming region. Out of the several curcumin to hydroxyquinol ratios studied, cocrystal formation was observed for mixtures containing curcumin mole fractions of 0.33 and 0.5. These curcumin−hydroxyquinol cocrystals were further characterized by powder X-ray diffraction analysis, DSC, scanning electron microscopy, Raman spectroscopy, Fourier transform infrared spectroscopy, and solid-state 13 C nuclear magnetic resonance spectroscopy. Intramolecular hydrogen bonding interactions in salicylic acid and weaker intermolecular interactions between hydroxyl (-OH) group present at the ortho position of salicylic acid with the keto (-CO) group of curcumin result in a generation of eutectic, whereas strong hydrogen bonding interactions between hydroxyl -OH groups present in hydroxyquinol molecule and curcumin molecule result in formation of cocrystal upon melting and recrystallization. These curcumin−salicylic acid eutectic and curcumin−hydroxyquinol cocrystals show faster powder dissolution rates than raw curcumin. In the case of curcumin−hydroxyquinol cocrystals, cocrystals containing a curcumin mole fraction of 0.33 showed enhanced dissolution than cocrystals containing a curcumin mole fraction of 0.5.

Precipitation of curcumin, a poorly water-soluble drug, has been carried out by the liquid antisolvent technique in the presence of ultrasound and stabilizers. Curcumin particles with varied morphology were observed to have formed during precipitation in the presence of ultrasound and additives such as sodium dodecyl sulfate (SDS), Tween 80, hydroxyl propyl methylcellulose (HPMC), polyvinyl pyrrolidone (PVP), and bovine serum albumin (BSA). Characterization of the precipitated particles reveals that curcumin particles precipitated with ultrasound and large polymeric stabilizers such as HPMC, PVP, and BSA are superstructures formed by aggregation of several primary curcumin nanoparticles. The particles in these cases appeared to be loose aggregates (of~1-5 μm in size) composed of several curcumin nanoparticles (~50-200 nm in size). On the other hand, curcumin particles precipitated in the presence of ultrasound and without additive as well as small-molecule stabilizers like SDS and Tween 80 appear more fused (the primary building blocks of these particles were not clearly visible). Moreover, curcumin particles precipitated in the presence of ultrasound only and particles precipitated in the presence of ultrasound along with additives were found to exist in the orthorhombic form, whereas raw curcumin and curcumin particles precipitated without any additive and without ultrasound were found to exist in the monoclinic form. The results obtained in this work suggest that curcumin particles with the desired physical form and morphology can be engineered through a careful manipulation/choice of ultrasound and additives during precipitation. [6][7][8] DL-glutamic acid, 11 and 11102 | CrystEngComm, 2014, 16, 11102-11114 This journal is † Electronic supplementary information (ESI) available: Experimental materials and methods, table on precipitated curcumin form details, comparative XRPD patterns of form 1, form 2 and form 3 with the precipitated curcumin particles, hydrogen bonding in different curcumin forms, FTIR spectra of precipitated curcumin particles, and the SEM micrograph of raw curcumin. See

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