Sameer V. Dalvi

Partial molar volume fraction of solvent in binary (CO2–solvent) solution for solid solubility predictions

Prediction of solid solute solubility in an organic solvent with dissolution of dense CO2 as antisolvent is important for the design of antisolvent crystallization processes. A new model is proposed in this work to predict the mole fraction of a pure solid solute in a ternary (CO2–solvent–solid) system at solid–liquid equilibrium. This is based on the hypothesis that CO2 molecules cluster around the solvent molecules at high values of CO2 mole fraction. As a result the solvent molecules proportionately lose their affinity for the solid solute molecules. Accordingly the solid mole fraction in a solution is considered to be proportional to the partial molar volume fraction (PMVF) of the solvent in the binary (CO2–solvent) liquid solution or the solvents contribution to the molar volume of the binary system. This model enables prediction of the liquid phase composition of the ternary system using only the binary information. The model has been validated, by predicting the solid solubility in various organic solvents, in good agreement with the corresponding experimental data from the literature, for several solids, such as β-carotene, cholesterol, acetaminophen, as well as naphthalene, phenanthrene and salicylic acid. The performance of this model is found to be better than an earlier method, which uses the partial molar volume (PMV) of solvent in the CO2–solvent mixture.

Effect of ultrasound and stabilizers on nucleation kinetics of curcumin during liquid antisolvent precipitation.

Nucleation kinetics of liquid antisolvent precipitation of a poorly water soluble drug curcumin in presence of ultrasound and surfactants have been estimated. Ultrasound and stabilizers were found to have opposing effects on induction time (τ ind), metastable zone width (MSZW) and nucleation rates (J) of curcumin during antisolvent precipitation. The use of ultrasound (in presence or absence of stabilizers) was found to decrease τ ind and MSZW drastically while the values of nucleation rates were found to increase. In contrast to these observations, use of stabilizers (in presence or absence of ultrasound) were found to increase MSZW, increase τ ind and lower the nucleation rates (J) of curcumin. The solid-liquid interfacial energies (γSL) for curcumin in aqueous ethanolic solutions (with and without stabilizers) have also been calculated using experimentally estimated induction time (τ ind) and supersaturation data. The values of solid-liquid interfacial energies were found to be in the range of 1.5-3.5 mJ/m(2). In comparison to these values, the values of γSL predicted by Mersmann equation and equation proposed by Bennema and Sohnel were found to be significantly higher and were in the range of 10-30 mJ/m(2).

Ultrasound-assisted modulation of concomitant polymorphism of curcumin during liquid antisolvent precipitation.

Curcumin polymorphs were found to precipitate concomitantly during liquid antisolvent precipitation. While, commercially available curcumin exists in a monoclinic form, the curcumin particles when precipitated in presence of additives and ultrasound were either found to be the mixtures of orthorhombic (Form 3) and monoclinic form (Form 1) or were found to be in orthorhombic form (Form 3) or monoclinic form (Form 1). The experimentally observed particle morphologies did not match clearly with the predicted BFDH morphologies of curcumin and the experimentally observed morphologies were more elongated as compared to the predicted BFDH morphologies. At lower ultrasonic irradiation times, the monoclinic form (Form 1) was found to dominate the mixture of particles. However, an increase in ultrasonic irradiation time was found to increase the percentage of orthorhombic form (Form 3) in the particles indicating that the increase in ultrasonic energy facilitates formation of orthorhombic form over the monoclinic form, irrespective of the additive used. These results therefore suggest that the ultrasonic energy can be effectively used to manipulate the polymorphic outcome of the precipitation.

Synthesis, characterization and stability of BSA-encapsulated microbubbles

In this work, we present an account of experimental studies performed for the synthesis, shelf stability and in vitro stability of microbubbles made from perfluorobutane (PFB) gas and coated in a shell of Bovine Serum Albumin (BSA). These microbubbles were produced by probe sonication method using formulations containing BSA, caprylic acid (CA) and N-acetyl-DL-tryptophan (Tryp) in different combinations. The freshly prepared polydisperse (0.5–20 μm) microbubble samples were then size isolated by centrifugal differentiation to produce microbubble suspensions with a narrow size range of 3 to 5 μm. Among all the different combinations of BSA, CA and Tryp used, the formulation containing BSA and Tryp yields microbubbles with a maximum shelf life (of ∼8 months). This stability was observed when microbubbles were stored in an aqueous solution (80% v/v) consisting of the original solution [which contains BSA and Tryp dissolved in phosphate buffer saline (PBS)] used to make the microbubbles, 1,2-propane-diol (10% v/v) and glycerin (10% v/v). Fluorescence and Circular Dichroism (CD) spectroscopic analyses were carried out to study the effect of additives such as CA and Tryp, and heating and sonication on the secondary and tertiary structure of BSA. It was found that the use of Tryp in the formulation favors greater unfolding of BSA as compared to CA. This in addition to a lower diffusivity of PFB, and lower solubility of BSA in the solution containing Tryp leads to a relatively stable microbubble suspension. Microbubbles produced using different BSA formulations were mixed with PBS at 37 °C to check in vitro stability of the microbubbles. It was observed that microbubbles produced from BSA and Tryp persisted longer than other microbubbles. In addition to this, in vitro ultrasonography (USG) carried out using freshly prepared microbubbles and microbubbles stored for around 4 months also yielded promising results.

Engineering Cocrystals of Poorly Water-Soluble Drugs to Enhance Dissolution in Aqueous Medium

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.

Continuous production of aqueous suspensions of ultra-fine particles of curcumin using ultrasonically driven mixing device

Abstract Developing drug formulations for poorly water-soluble drugs is a major challenge for pharmaceutical industries as the poor water solubility limits bioavailability of these drugs. Production of nanoparticles/microparticles of these drugs is one of the ways to improve dissolution rates by increasing interfacial area for dissolution. Curcumin, a compound obtained from the rhizome of curcuma longa (turmeric roots), is a pharmaceutically viable molecule. However, poor aqueous solubility limits its therapeutic use. In this work, we report studies conducted to continuously produce aqueous suspensions of curcumin nano/micro particles. Influence of process parameters such as ultrasound, additives, and solvent to antisolvent ratio on polymorphic outcome and morphology of precipitated particles has been investigated. Ultrasound was found to greatly influence the polymorphic form and the morphology of precipitated particles. Nucleation rates, mixing time, and solid–liquid interfacial energies were also estimated to understand the effect of various processing parameters on the precipitation process. Graphical Abstract

Microbubble-Mediated Enhanced Delivery of Curcumin to Cervical Cancer Cells

The major bottleneck in the current chemotherapy treatment of cancer is the low bioavailability and high cytotoxicity. Targeted delivery of drug to the cancer cells can reduce the cytotoxicity and increase the bioavailability. In this context, microbubbles are currently being explored as drug-delivery vehicles to effectively deliver drug to the tumors or cancerous cells. Microbubbles when used along with ultrasound can enhance drug uptake and inhibit the growth of tumor cells. Several potential anticancer molecules exhibit poor water solubility, which limits their use in therapeutic applications. Such poorly water soluble molecules can be coadministered with microbubbles or encapsulated within or loaded on the microbubbles surface, to enhance the effectiveness of these molecules against cancer cells. Curcumin is one of such potential anticancer molecules obtained from the rhizome of herbal spice, turmeric. In this work, curcumin-loaded protein microbubbles were synthesized and examined for effective in vitro delivery of curcumin to HeLa cells. Microbubbles in the size range of 1–10 μm were produced using perfluorobutane as core gas and bovine serum albumin (BSA) as shell material and were loaded with curcumin. The amount of curcumin loaded on the microbubble surface was estimated using UV–vis spectroscopy, and the average curcumin loading was found to be ∼54 μM/108 microbubbles. Kinetics of in vitro curcumin release from microbubble surface was also estimated, where a 4-fold increase in the rate of curcumin release was obtained in the presence of ultrasound. Sonication and incubation of HeLa cells with curcumin-loaded BSA microbubbles enhanced the uptake of curcumin by ∼250 times. Further, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay confirmed ∼71% decrease in cell viability when HeLa cells were sonicated with curcumin-loaded microbubbles and incubated for 48 h.

Understanding rationale behind carbamazepine co-crystallization with acids, amides and hydrazides

Carbamazepine is an active pharmaceutical ingredient with anticonvulsive properties. Cocrystallization is of an API helps in fine tuning its solid-state properties such as shelf life, melting point, solubility, dissolution and bioavailability. Cocrystallization of carbamazepine with several structurally-related coformers belonging to class of amides and acids has been widely studied till date. However, an indepth understanding of rationale behind carbamazepine cocrystallization with acids or amides has not been exposed yet. Also, the potential of hydrazides to form cocrystals with carbamazepine has not been investigated yet. In this work, we propose to understand the rationale behind carbamazepine cocrystallization with different structurally related coformers. Dicarboxylic acids (Pimelic acid, suberic acid, azelaic acid, sebacic acid), tricarboxylic acids (Trimellitic acid), carboxamides (acetamide, salicylamide and p-hydroxybenzamide) and hydrazides (niazid, isoniazid and maleic acid hydrazide) has been used as coformers for our study. The role of number of C atoms in dicarboxylic and tricarboxylic acids, the influence of aromatic rings present in amides and the influence of –R functional group in hydrazides in cocrystallization process has been investigated in detail. Our experimental observations illustrated that some systems result in cocrystals whereas some others result into eutectics or physical mixtures. Succinic acid tends to form cocrystals whereas suberic acid resulted in eutectic as a consequence. Similarly, benzamide resulted in cocrystal whereas acetamide resulted in a physical mixture based on the DSC thermograms. An indepth understanding is being developed to identify the rationale responsible for cocrystallization with further characterization techniques. Hence, we suggest that conducting a thorough study to understand the rationale behind cocrystallization can be implemented to different drug systems which can further simplify the cocrystal screening process for structurally-related drugs in a pharmaceutical industry.