Formation of Hemihydrate Crystal form Overcomes Milling Issue Induced by Exposed Functional Groups on Cleavage Plane for a Y5 Receptor Antagonist of Neuropeptide Y.

This study aimed to investigate the crystal forms of an originally designed Y5 receptor antagonist of neuropeptide Y. Polymorphic screening was performed via solvent evaporation and slurry conversion using various solvents. The obtained crystal forms α, ß, and γ were characterized by X-ray powder diffraction analysis. Thermal analysis determined that forms α, ß, and γ were hemihydrate, metastable and stable forms, respectively; the hemihydrate and the stable forms were candidates. To arrange the particle size, forms α and γ were subjected to jet milling. However, form γ could not be milled because of powder stiction to the apparatus, whereas form α could be. To investigate this mechanism, single-crystal X-ray diffraction analysis was performed. The crystal structure of form γ was characterized by two-dimensional hydrogen bonding between neighboring molecules. This revealed that the functional groups forming hydrogen bonds were exposed on the cleavage plane of form γ. The three-dimensional hydrogen-bonding network with water stabilized the hemihydrate form, α. These results indicate that the hydrogen bondable groups exposed on the cleavage plane of form γ should result in stiction of the powder and adherence to the apparatus. It was concluded that crystal conversion is a method to overcome the milling issue.

Influence of solvent choice and operating conditions on Chlorzoxazone crystal shape and size

Abstract Solubility of pharmaceutical drugs in organic solvents is one of the important parameters to understand the equilibrium concentration of solute-solvent, which helps optimize and design crystallization conditions to obtain the desired product crystals. In the present study, Chlorzoxazone (CHZ) is used as a model pharmaceutical compound to investigate the equilibrium solubility, the influence of solvent and the operating conditions on the shape, and the size distribution. The solubility of CHZ is determined in organic solvents like Isopropanol, Ethanol, and 2-Ethoxyethylacetate, Ethylacetate and Ethyllactate using shake flask method from -5ºC to 60ºC. The solubility of CHZ in these solvents shows an increasing trend as the temperature increases in the following order: ethyllactate + water (0.5+0.5) < ethylacetate < isopropanol < ethanol < 2-ethoxyethylacetate < ethyllactate + water (0.75+0.25). The solvents, isopropanol, ethanol, and ethyl lactate, produce needle-shaped crystals, while 2-ethoxyethylacetate and ethyl acetate tend to produce plate shaped crystals. CHZ crystals obtained from 2-ethoxyethylacetate tend to have plate shaped crystals with a lower aspect ratio and are selected for batch cooling crystallization experiments performed at different cooling rates, and agitation. It is found that the agitation at 300 rpm and the cooling rate 0.2ºC/min produce more uniform crystal size distribution

Prediction of Mefenamic Acid Crystal Shape by Random Forest Classification.

OBJECTIVE: Particle shape can have a significant impact on the bulk properties of materials. This study describes the development and application of machine-learning models to predict the crystal shape of mefenamic acid recrystallized from organic solvents. METHODS: Crystals were grown in 30 different solvents to establish a dataset comprising solvent molecular descriptors, process conditions and crystal shape. Random forest classification models were trained on this data and assessed for prediction accuracy. RESULTS: The highest prediction accuracy of crystal shape was 93.5% assessed by fourfold cross-validation. When solvents were sequentially excluded from the training data, 32 out of 84 models predicted the shape of mefenamic acid crystals for the excluded solvent with 100% accuracy and a further 21 models had prediction accuracies from 50-100%. Reducing the feature set to only solvent physical property descriptors and supersaturations resulted in higher overall prediction accuracies than the models trained using all available or another selected subset of molecular descriptors. For the 8 solvents on which the models performed poorly (< 50% accuracy), further characterisation of crystals grown in these solvents resulted in the discovery of a new mefenamic acid solvate whereas all other crystals were the previously known form I. CONCLUSIONS: Random forest classification models using solvent physical property descriptors can reliably predict crystal morphologies for mefenamic acid crystals grown in 20 out of the 28 solvents included in this work. Poor prediction accuracies for the remaining 8 solvents indicate that further factors will be required in the feature set to provide a more generalized predictive morphology model.

Cediranib Maleate-From Crystal Structure Toward Materials Control.

Cediranib maleate is an active pharmaceutical ingredient (API) in phase III of development within AstraZeneca's oncology portfolio. Analysis of the crystal structure of this API confirmed that the selected salt form was robust. The salt formation step had to be redesigned to avoid an unwanted metastable polymorph. A solvate with a twist appeared during later development and was avoided using insights gained from its crystal structure. Differences between predicted and experimental aspect ratios correlate with weaker crystal interactions. Acceptable variability in particle size was defined and accommodated. The "Matwall" is introduced as a tool for building control of API performance from the crystal structure upward.

A Compact Device for the Integrated Filtration, Drying, and Mechanical Processing of Active Pharmaceutical Ingredients.

Recent changes in the pharmaceutical sector call for the development of novel manufacturing approaches to reduce costs and improve control over product quality. In this area, the development of compact, plug-and-play devices that fit in a continuous manufacturing system has gained interest in recent years. Most Nutsche filters offer a versatile solution as compact filtration and drying devices. However, conventional drying processes tend to generate a large amount of lumps, usually requiring further mechanical processing of the isolated drug substance before it can be formulated. In this work, we present a compact, automatable filtration device that takes advantage of a unique impeller design and in situ measurements of the drying heat duty to integrate mechanical processing into the drying step. By preventing the formation of dry lumps during drug substance drying, and breaking needle-like crystals through the developed agitation program, the resulting powder can be directly used for tablet formulation. This device, designed to fit in a compact continuous manufacturing module, has the potential to reduce manufacturing costs and footprint, while allowing for the low-shear mechanical processing of heat-sensitive compounds.

Crystallization Velocity and UV Performance of Formulations With Oversaturated UV-Filter Content.

Cosmetic oils are used to dissolve crystalline lipophilic UV filters; however, little knowledge exists about the effect of other formulation ingredients. This study investigates the influence of emulsifiers on the recrystallization speed of 4 UV filters and the impact of UV-filter crystal formation on delivered performance. The crystallization pattern of studied UV filters was assessed using X-ray diffractometry, whereas their recrystallization speed in formulations with various emulsifiers was monitored microscopically. UV-filter concentration was above the saturation level to promote recrystallization. Furthermore, to understand the kinetics of recrystallization, the conformer number of each UV-filter was calculated. For the impact on performance, the absorbance of a sunscreen was measured before and after recrystallization of the contained UV filter. This study confirmed the crystallinity of tested UV filters. The emulsifier was shown to influence the UV-filter recrystallization speed in emulsions. Continuous oil phase sunscreens were critical; all UV filters recrystallized promptly in oils and water-in-oil emulsions. Large molecule UV filters showed slowest recrystallization speed explained by a higher number of possible conformers. Finally, this work confirmed the negative impact of crystal formation on the delivered photoprotection of a sunscreen.

Dropwise Additive Manufacturing of Pharmaceutical Products Using Particle Suspensions.

The principal method of drug delivery is by oral solid doses, the production of which often necessitates multiple post-crystallization unit operations to ensure content uniformity or enhance bioavailability. As an alternative to conventional dose production methods, applications of additive manufacturing technologies based on solvent- or melt-based formulations have demonstrated the potential for improvements to process efficiency, flexibility, and dosing precision. Here we explore the use of particulate suspensions in a dropwise additive manufacturing process as a method for dosing active ingredients in crystalline form, which may be difficult to achieve via powder processing due to poor flow properties. By employing a fluid-based method, powder flow issues are alleviated and adaptation of the process to new particles/crystals is facilitated by dimensional analysis. In this work, a feasibility study was conducted using 4 active ingredient powders, each with non-ideal particle properties, and 2 carrier fluids, in which the active ingredient does not dissolve, to formulate suspensions for dose manufacturing; drug products were analyzed to show reproducibility of dosing and to assess preservation of particle size through the process. Performance across particle types is affected by particle size and shape, and is related through effects on the rheological properties of the formulation.

Role of Solvent Selection on Crystal Habit of 5-Aminosalicylic Acid-Combined Experimental and Computational Approach.

Many active pharmaceutical ingredients exhibit a needle-like (acicular) crystal habit, which can significantly complicate their downstream processing. In this study, the acicular crystal habit of a model active pharmaceutical ingredient, 5-aminosalicylic acid (5-ASA), was modified by addition of selected organic solvents to the typical aqueous crystallization process. 5-ASA was crystallized by a pH shift from 7.5-8 to 4 in the presence of methanol, acetonitrile, acetone, tetramethylurea, tetrahydrofuran or dimethyl sulfoxide at 25% v/v, or butanol at 9% v/v. Changes to the experimentally observed crystal habit are rationalized by considering adsorption energy calculations for the solvent molecules onto the morphologically important crystal faces. The crystal habit was influenced most significantly by organic solvents containing a good H-bond acceptor atom, particularly oxygen in acetone, tetramethylurea, tetrahydrofuran, and dimethyl sulfoxide. Such solvents have strongly stabilizing adsorption energies onto the fast-growing crystal faces, and their presence in solution thereby serves to modify the acicular habit of 5-ASA. The developed knowledge base on crystal interface-solvent interactions can form a basis for further engineering of an optimal crystal habit for 5-ASA.

How does your crystal grow? A commentary on Burton, Cabrera and Frank (1951) 'The growth of crystals and the equilibrium structure of their surfaces'.

The key ideas presented in the classic paper 'The growth of crystals and the equilibrium structure of their surfaces' by W. K. Burton, N. Cabrera and F. C. Frank, published in Philosophical Transactions A in 1951, are summarized and put in the context of both the state of knowledge at the time of publication and the considerable amount of work since that time that has built on and developed these ideas. Many of these developments exploit the huge increase in the capabilities of computer modelling that complement the original analytic approach of the paper. The dearth of relevant experimental data at the time of the original publication has been transformed by the application of increasingly sophisticated modern methods of surface science. This commentary was written to celebrate the 350th anniversary of the journal Philosophical Transactions of the Royal Society.

Application of image-based particle size and shape characterization systems in the development of small molecule pharmaceuticals.

With the introduction of Quality by Design (QbD) to the pharmaceutical industry, there has been an increased focus on understanding the nature of particles and composites, with the aim of understanding and modeling how they interact in complex systems, leading to robust dosage forms. Particle characterization tools have evolved and now enable a greater level of understanding of powder systems and blends. Tools that can elucidate the size and shape of particulate systems can provide significantly more information about the nature of the particles being analyzed, than a conventional particle size measurement. Although accurate size and shape analysis has always been regarded as the "gold standard" in understanding the nature of particulate systems, neither imaging systems nor IT infrastructure was sufficiently developed to allow this to be performed with sufficient accuracy in a timely manner. The aim of this review is to provide an insight into developments in the field of size and shape analysis of pharmaceutical systems, and how these can now realistically be used as robust development tools. Examples of current uses of such technologies will be explored as well as investigating future applications such as combined image/spectroscopic analyses to track single components within blended systems.

Opposite face sensitivity of CeO2 in hydrogenation and oxidation catalysis.

The determination of structure-performance relationships of ceria in heterogeneous reactions is enabled by the control of the crystal shape and morphology. Whereas the (100) surface, predominantly exposed in nanocubes, is optimal for CO oxidation, the (111) surface, prevalent in conventional polyhedral CeO2 particles, dominates in C2H2 hydrogenation. This result is attributed to the different oxygen vacancy chemistry on these facets. In contrast to oxidations, hydrogenations on CeO2 are favored over low-vacancy surfaces owing to the key role of oxygen on the stabilization of reactive intermediates. The catalytic behavior after ageing at high temperature confirms the inverse face sensitivity of the two reaction families.