Examining solution and solid state composition for the solution mediated polymorphic transformation of carbamazepine and piracetam

peer-reviewedSolution mediated polymorphic transformations (SMPT) of the pharmaceutical compounds carbamazepine and piracetam have been investigated. Seeded transformation experiments were performed, and the solution concentration was monitored by in situ infra-red spectroscopy using a calibration free method. Solid samples were also taken over time, and the percentage of metastable and stable polymorphic phases were determined using off line quantitative powder X-ray diffraction analysis. Solution and solid state data were compared for each compound. In the case of carbamazepine, the SMPT from FI to FIII was identified as being controlled by the growth of the stable FIII polymorph. For piracetam, the SMPT was also identified as being controlled by growth of the stable polymorph, but with a more considerable induction time for nucleation of the stable phase. This paper demonstrates how the rate determining steps of the SMPT can be identified if both solution and solid phase data are recorded. The results are compared with other studies reported in the literature and rationalized into four principal scenarios

Isothermal Suspension Conversion as a Route to Cocrystal Production: One-Pot Scalable Synthesis

Isothermal suspension conversion is presented as a suitable method for the manufacture of pure cocrystal products once the ternary phase diagram (TPD) for the cocrystal system in the desired solvent is available. One:one and 3:2 cocrystals of <i>p</i>-toluenesulphonamide/triphenylphosphine oxide were produced in acetonitrile and dichloromethane using this method. Eight individual batches of product were prepared with complete conversion to pure product achieved in seven batches. Product recovery (77–99%), reaction conversion (17–89%), and volumetric productivity (0.03–0.63 g/cm³) were calculated for each product batch. These parameters are essentially determined by the batch operating mass fraction composition selected from the TPD, allowing for tailoring of processing conditions to suit process requirements and capabilities by careful selection of the optimum operating mass fraction composition

Creating cocrystals: a review of pharmaceutical cocrystal preparation routes and applications

Originally discovered almost a century ago, cocrystals continue to gain interest in the modern day due to their ability to modify the physical properties of solid-state materials, particularly pharmaceuticals. Intensification of cocrystal research efforts has been accompanied by an expansion of the potential applications where cocrystals can offer a benefit. Where once solubility manipulation was seen as the primary driver for cocrystal formation, cocrystals have recently been shown to provide attractive options for taste masking, mechanical property improvement, and intellectual property generation and extension. Cocrystals are becoming a commercial reality with a number of cocrystal products currently on the market and more following in registration and clinical trial phases. Increased commercialization of cocrystals has in turn necessitated additional research on methods to make cocrystals, with particular emphasis placed on emerging technologies that can offer environmentally attractive and efficient options. Methods of producing cocrystals and of harnessing the bespoke physical property adjustment provided by cocrystals are reviewed in this article, with a particular focus on emerging trends in these areas

Pharmaceutical cocrystals: from serendipity to design to application

The field of pharmaceutical cocrystals has reached a tipping point, particularly because cocrystals can improve the physicochemical properties of drugs without compromising their therapeutic benefit. Accounts of cocrystal investigations in the literature started in earnest in 2003 and patent applications soon followed. The frequency of both has steadily accelerated, demonstrating an enhanced understanding of the design, characterisation, and manufacture of cocrystals and heightened interest from industry. Indeed, there were four new product approvals from 2014 to 2017 and more are in the pipeline. Here, we review all marketed drug products that are based upon pharmaceutical cocrystal drug substances, starting with the first recorded example, Beta-Chlor® in 1963, with a particular emphasis on their discovery, rationale for use, and market impact

Solution mediated phase transformations between co-crystals

A solution mediated transformation between two co-crystal phases has been observed for the p-5 toluensulfonamide/triphenylphosphine oxide co-crystal system. This system has two known co-crystals with 1:1 and 3:2 stoichiometry respectively, and the ternary phase diagram (TPD) for the system has been determined in acetonitrile previously. By manipulating the solution composition in this 10 solvent to a region of the TPD where the 1:1 co-crystal is stable, the 3:2 co-crystal could be observed to convert to the 1:1 co-crystal. The corresponding transformation was true for the 1:1 co-crystal in a region of the TPD where the 3:2 co-crystal is stable; the 1:1 co-crystal converted to the 3:2 co-15 crystal

Formulating a stable mannitol infusion while maintaining hyperosmolarity

Mannitol infusion is commonly used in the treatment of intracranial hypertension following traumatic brain injury. It has long been known to have stability issues, specifically, mannitol recrystallises from solutions greater than 10% w/v in ambient conditions. This can happen at any time, whether on the pharmacy shelf or during a medical procedure. This study describes the stability limits of 20% w/v mannitol infusion (the most common strength used clinically) and proposes a number of safer, stable and tuneable hyperosmotic formulations of mannitol in combination with clinically acceptable osmotic agents (NaCl, sorbitol and glycerol)

Solution-Mediated Polymorphic Transformation of FV Sulphathiazole

The solution-mediated polymorphic transformation of FV sulphathiazole was investigated in ethanol at 10 °C. Powder X-ray diffraction (PXRD) identified the transformation product as a mixture of FII and FIV sulphathiazole. This mixture remained stable in solution at 10 °C with agitation for 24 h. In situ temperature controlled optical microscopy enabled visualization of the transformation in real time, allowing elucidation of the transformation mechanism. A modest amount of dissolution of FV sulphathiazole preceded the nucleation of FII and FIV crystals, which were detected simultaneously. Thereafter, these polymorphs grew rapidly. Experimental evidence is presented for a mechanism, whereby nucleation of FII and FIV was initiated on the roughened surface of the dissolving FV crystals, without any indication for a spatially extended structural relationship between the host form V and the nucleating phases. Subsequent growth of FII and FIV crystals consumed the remaining FV crystals completing the dissolution-recrystallization mechanism

Examining solution and solid state composition for the solution mediated polymorphic transformation of carbamazepine and piracetam

Solution mediated polymorphic transformations (SMPT) of the pharmaceutical compounds carbamazepine and piracetam have been investigated. Seeded transformation experiments were performed, and the solution concentration was monitored by in situ infra-red spectroscopy using a calibration free method. Solid samples were also taken over time, and the percentage of metastable and stable polymorphic phases were determined using off line quantitative powder X-ray diffraction analysis. Solution and solid state data were compared for each compound. In the case of carbamazepine, the SMPT from FI to FIII was identified as being controlled by the growth of the stable FIII polymorph. For piracetam, the SMPT was also identified as being controlled by growth of the stable polymorph, but with a more considerable induction time for nucleation of the stable phase. This paper demonstrates how the rate determining steps of the SMPT can be identified if both solution and solid phase data are recorded. The results are compared with other studies reported in the literature and rationalized into four principal scenarios

Formation of ciprofloxacin–isonicotinic acid cocrystal using mechanochemical synthesis routes—an investigation into critical process parameters

The mechanochemical synthesis of cocrystals has been introduced as a promising approach of formulating poorly water-soluble active pharmaceutical ingredients (APIs). In this study, hot-melt extrusion (HME) as a continuous process and grinding and ball milling as batch processes were employed to explore the feasibility of cocrystallization. Ciprofloxacin (CIP) and isonicotinic acid (INCA) were selected as the model API and coformer. CIP–INCA cocrystal was produced in all techniques. It was revealed that higher cocrystal content could be achieved at longer durations of grinding and ball milling. However, milling for more than 10 min led to increased co-amorphous content instead of cocrystal. A design of experiment (DoE) approach was used for deciphering the complex correlation of screw configuration, screw speed, and temperature as HME process parameters and their respective effect on final relative cocrystal yield. Statistical analysis showed that screw configuration, temperature, and their interaction were the most critical factors affecting cocrystallization. Interestingly, screw speed had minimal impact on the relative cocrystallization yield. Cocrystallization led to increased dissolution rate of CIP in phosphate buffer up to 2.5-fold. Overall, this study shed a light on the potential of mechanochemical synthesis techniques with special focus on HME as a continuous process for producing cocrystals