Selective polymorph transformation via solvent-drop grinding (original) (raw)
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Therapeutic Delivery, 2014
The active pharmaceutical ingredient (API) of a dosage form is affected by number of mechanical and environmental factors which have a tendency to alter its crystalline state. Polymorphic transitions have been observed to occur during various unit operations like granulation, milling and compression. Forces of pressure, shear and temperature have an ability to induce alterations in crystal habit. A conversion in polymorphic form during a unit operation is very likely to affect the handling of API in the subsequent unit operation. Transitions have also been observed during storage of formulations where the relative humidity and temperature play a major role. An increase in temperature during storage can dehydrate or desolvate the crystal and hence produce crystal defects, whilst, high humidity conditions produce higher molecular mobility leading to either crystallization of API or alteration of its crystalline form.
Advanced Drug Delivery Reviews, 2004
The concepts of high-throughput (HT) screening and combinatorial synthesis have been integrated into the pharmaceutical discovery process, but are not yet commonplace in the pharmaceutical development arena. Emerging strategies to speed pharmaceutical development and capture solid form diversity of pharmaceutical substances have resulted in the emergence of HT crystallization technologies. The primary type of diversity often refers to polymorphs, which are different crystal forms of the same chemical composition. However, diverse salt forms, co-crystals, hydrates and solvates are also amenable to study in HT crystallization systems. The impact of form diversity encompasses issues of stability and bioavailability, as well as development considerations such as process definition, formulation design, patent protection and regulatory control. This review highlights the opportunities and challenges of HT crystallization technologies as they apply to pharmaceutical research and development. D
Green solvent free methods for active pharmaceutical ingredient polymorph control
2018
Ten benzamidinium salts of carboxylic acids, amides and sulfonamides have been crystallized from solution. Single-crystal X-ray analyses revealed various hydrogen bonding motifs which are discussed in terms of supramolecular synthons and graph sets. Benzamidinium hydrogen maleate (5a) crystallizes as large needles of up to > 3 cm length. Attempts to influence the crystal habit and size through a change of solvent and the presence of additives yielded a second polymorph (5b). The formation of the benzamidinium salts by mechanochemical reaction was also investigated. Grinding of benzamidine with nicotinic acid, salicylic acid, paminobenzoic acid, cyanuric acid, pimelic acid, saccharin and sulfathiazole with mortar and pestle or using a ball-mill gave compounds identical to those obtained by crystallization from solution. Time-dependent X-ray powder patterns of a stoichiometric benzamidine/cyanuric acid mixture suggested that the mechanochemical salt formation occured via the amorph...
Crystallization of a polymorphic drug in a stirred tank
2007
The crystallization process of a drug exhibiting several polymorphic forms is investigated. The study focuses on one reference pharmaceutical crude product. The objective of the work presented in this paper is, on the one hand, to identify the mechanism of the polymorphic transition-from the unstable morph II to the stable morph I-, and, on the other hand, to investigate the influence of the mixing operating conditions on the kinetics of this transition. The study shows that the polymorphic transition follows a mechanism of dissolution (of the morph II)recrystallization (nucleation and growth of the morph I) mediated by the solvent. Moreover, experimental studies show that the step controlling the beginning of the polymorphic transition is the nucleation of the stable morph I. The mixing plays an important role in this kinetics as the mixing operating conditions influence the metastable zone width.
2004
Polymorphism in pharmaceutical solids is a major issue that has medical, financial and legal implications. There are many thermodynamics and kinetics factors which affect the polymorph selectivity during the crystallization process such as nucleation temperature, supersaturation and type of solvent. Among these parameters, type of solvent is a major kinetic factor that has drawn the attention of researchers. Literature is ripe with research showing the effect of solvent on the polymorph selectivity, mainly using the polar and non-polar terminology, but seldom the researchers have explained the effect of solvent at molecular level. This work looks into the effect of solvent and the corresponding intermolecular interactions on the polymorphic selectivity. Two case studies on the effect of solvent will be discussed for polymorphic systems of stearic acid (used for tablet coating) and ranitidine hydrochloride (H2-receptor antagonist drug). Introduction Polymorphism is the phenomenon tha...
Polymorphism and Polymorph Characterisation in Pharmaceuticals
Journal of Biomedical and Pharmaceutical Research, 2019
Polymorphism is the ability of a specific chemical compound to crystallize in more than one crystalline form. Polymorphs had a different arrangement of the molecule in the given crystal lattice and may properties such as packing properties, thermodynamic properties, spectroscopic properties, kinetic properties, surface properties and mechanical properties. Polymorph can be classified in various class such as crystalline, amorphous, hydrate and solvate. Polymorphs are categorized into two types, enantiotropes and monotropes, depending upon their stability with respect to the range of temperatures and pressures. There are various guidelines for the control of polymorphs in drug substances and drug product. Different analytical techniques are used for the detection, quantification and characterisation of the polymorphs in the drug substances and drug products. Control of polymorph in a drug substance and drug product is important for the safety and efficacy of the drug. Keywords: Poly...
Solid state crystallinity, amorphous state, and its implications in the pharmaceutical process
International Journal of Pharmaceutical Sciences and Research
Many drugs exist in crystalline solid form due to reasons of stability and ease of handling during the various stages of drug development. Crystalline solids can exist in the form of polymorphs, solvates or hydrates. Phase transitions such as polymorph inter-conversion, formation of hydrates, desolvation of solvates, and conversion of the crystalline to amorphous form may occur during various pharmaceutical processes. This could change the dissolution rate and transport characteristics of the drug. The current focus of research in the area is to understand the origins of polymorphism at the molecular level, and to predict and prepare the most stable polymorph of the drug. The aim of this review is to understand the recent development in the area of solid state crystallinity, amorphous state and to address the current challenges faced by pharmaceutical formulation, process development scientists and to anticipate future developments.
Transformation of Pharmaceutical Compounds upon Milling and Comilling: The Role of Tg
Journal of Pharmaceutical Sciences, 2007
Milling is a usual process used in the course of drug formulation, which however may change the physical nature of the end product. The diversity of the transformations of organic compounds upon milling has been widely demonstrated in the pharmaceutical literature. However, no effort has still been devoted to study the correlation between the nature of the transformation and the milling conditions. Results clarifying such transformations are shortly reviewed with special attention paid to the temperature of milling. The importance of the position of the glass transition temperature compared with that of milling is demonstrated. It is shown that decreasing the milling temperature leads to an increase of the amorphization tendency whereas milling above T g can produce a crystal-to-crystal transformation between polymorphic varieties. These observations contradict the usual suggestion that milling transforms the physical state only by a heating effect which induces a local melting. Equilibrium thermodynamics does not seem appropriate for describing the process. The driven alloys concept offers a more rational framework to interpret the effect of the milling temperature. Other results are also presented, which demonstrate the possibility for milling to form low temperature solid-state alloys that offer new promising ways to stabilize amorphous molecular solids.
Polymorphism in Processes of Crystallization in Solution: A Practical Review
Organic Process Research & Development, 2009
Here we review the polymorphism of organic molecules, obtained through batch crystallization in solution carried out in a stirred vessel. Preferential formation of a polymorph, crystal habit, and size depend strongly on the kinetics of the mechanisms involved. First, we recall the concepts of crystallization from solution. Second, phase transitions are introduced, discussed, and illustrated. Third, we focus on the development of batch-crystallization processes to obtain a given polymorph. Prerequisites are recalled, and experimental techniques used for the screening of polymorphs are presented. Recent developments in the determination of the kinetics of solution-mediated phase transition are reviewed, and the advantages and drawbacks of using process analytical technologies to monitor such transitions are discussed. Lastly, we present control strategies.