Polymorphs crystal forms

Hilfiker et al. at Solvias used carbamazepine (CBZ) as a model compound to describe the use of Raman microscopy to characterize crystal forms, including during solvent evaporation experiments [228], The spectra were processed into clusters by spectral similarity. The authors note that all published and several new crystal forms were identified during the study. Solvias HTS uses a specific set of crystallization protocols that have tended to produce new polymorphs. Hilfiker notes that Raman microspectroscopy is an ideal analytical tool for high-throughput discrimination between crystal structures. [229], The ability to collect spectra directly and automatically in a microtiter plate with or without solvent and during evaporation is a major advantage over many other techniques. 

Raman microspectroscopy is readily performed on multiple locations inside each well. As in other instances, the results might not be representative of the whole sample because of the small sample volume probed. Polarization effects can be pronounced, but may be mitigated by averaging the results from additional locations. An alternative is rotating the sample, but this usually is not practical for multiwell plates. Both options increase analysis time. Such problems appear to be minimized when handling bulk powders [222,223,230], Several vendors sell systems preconfigured for automated analysis of microtiter plates and are typically integrated with optical microscopy. 

The bottleneck in utilizing Raman shifted rapidly from data acquisition to data interpretation. Visual differentiation works well when polymorph spectra are dramatically different or when reference samples are available for comparison, but is poorly suited for automation, for spectrally similar polymorphs, or when the form was previously unknown [231]. Spectral match techniques, such as are used in spectral libraries, help with automation, but can have trouble when the reference library is too small. Easily automated clustering techniques, such as hierarchical cluster analysis (HCA) or PCA, group similar spectra and provide information on the degree of similarity within each group [223,230]. The techniques operate best on large data sets. As an alternative, researchers at Pfizer tested several different analysis of variance (ANOVA) techniques, along with descriptive statistics, to identify different polymorphs from measurements of Raman 

After a potential drug has been identified, it is subjected to additional experiments, such as different solvents, temperatnres, and pressures, to understand its specific behavior. Initial studies sought to identify the presence of different polymorphs, but the need to quantify the polymorphs naturally arose. Subsequent work tested the quantification models and probed how the polymorph concentration changes as a function of time or other variables. Kinetic or rate parameters often can be extracted. Studies were performed on the laboratory scale, such as under a microscope or in a bench crystallizer, up to large-scale manufacturing trials. 

The stability of a suspension-emulsion of benzimidazole in oil was evaluated by quantifying the fractions of polymorphs A, B, and C as soon as prepared and after one year using a calibration model developed using pure polymorph samples [233]. The concentrations of mannitol in its amorphous form and each of three polymorphs were determined within 5% mass fraction, relative to salmon calcitonin [234]. The powders all were sized for delivery by respiration, less than 5 tan. 

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Crystal phase transitions are a possible target with present day computational means, when the transition is a smooth one and does not involve melting of the mother phase and subsequent recrystallization into the daughter phase. For crystalline OL-norleucine, an MD simulation has provided a detailed picture of the mechanism of a solid-solid second-order transition between two polymorphic crystal forms, showing concerted molecular displacements involving entire bilayers [61]. 

Detailed inspection of the crystal structure of 84 revealed that there is a certain space between reacting molecules in the crystal to allow initiation of photodimerization. The space, designated as a buffer zone , buffers the steric hindrance from which the reacting molecules suffer when they approach each other. The buffer zone is formed by the disordered piperidine rings in 84, but there is no extra space in the crystal structure of 83, and therefore photodimerization does not occur. Further evidence of this buffer zone was later reported by the same group, whereby polymorphic crystal forms had different reactivities toward photodimerization <1998BCJ321>. 

Several patents have recently published that claim the preparation of several different hydrates and polymorphic crystal forms of olanzapine. Dr. Reddy s Laboratories has recently disclosed the preparation of the monohydrate and the dihydrate of olanzapine. A mixture of 24 and A-methylpiperazine was refluxed in DMSO and toluene and then cooled (Scheme 8). Water was added and the precipitate was filtered and washed with water. The resulting solid was placed under vacuum at 30 to 50 °C to give the monohydrate or at ambient temperature to give the dihydrate. Recrystallization of crude olanzapine or one of its hydrates from CH2CI2 provided crystal form 1, whereas recrystallization from EtOAc provides crystal form 2. 

As detailed by Koradia et al. [16], the DSC and TGA studies were run at a heating rate of 10 °C / min, and a nitrogen purge was set at 80 ml / min for the DSC work and at 20 ml/min for the TGA work. The DSC thermogram of Form-I consisted of three endothermic transitions, with temperature maxima at 181, 186, and 190 °C. The DSC thermogram of Form-II also consisted of three endotherms, characterized by temperature maxima at 177,179, and 182 °C. During the TGA analysis, no temperature-induced loss of mass was observed for either polymorph, indicating that the two polymorphic crystal forms were anhydrous and nonsolvated. 

Ethyl acetate has also been shown to increase the solubility of chlortalidone and to modify the polymorphic crystal forms obtained for piroxicam pivalate and mefenamic acid, and has been used in the formulation of microspheres.Its use as a chemical enhancer for the transdermal iontophoresis of insulin has been investigated. 

For the work reported here, the polymorphic forms of the crystals of all the palm oil products at the temperatures measured are either in the 3 or 3 form or a mixture of both. The 3 polymorphic crystal form is plate-like while the 3 crystal form is spherulitic with needle-like projections from the center of the crystal as can be seen from the electron microscope pictures published by van Putte and Bakker (12). Therefore it can be seen that for the P polymorph, although the final overall shape of the crystal assumes the shape of a sphere in three dimensions, the plates or leaves that form the crystal are thin. This shows that as far as the actual growing sites of the crystal are concerned, growth is in two and not in three dimensions. 

Besides diastereoisomerism, iodinated radiopaques may show polymorphism crystals formed under different conditions show identical infrared absorption bands but with different intensities (262,263). 

Enthalpy differences between polymorphic crystal forms of the same substance [18,19] can be directly measured by calorimetry or by the difference in enthalpies of dissolution. A critical survey of these experiments shows that these enthalpy differences are very small, of the order of 0-10 kj mol-1, as expected since they must be a small fraction of the enthalpy of melting. In many cases the measured value is undistinguishable from experimental noise. These enthalpy differences can be estimated by just taking the differences in lattice energy between pairs of crystal phases whose complete structure is known, but the intrinsic uncertainty of such a calculation is also of the same order of magnitude of the property it tries to simulate. 

PGME crystallizes from melt in an a-like crystal form and PGME with mixed fatty acid compositions are not polymorphic. Synthetically produced PGME based on pure fatty acids, however, does show polymorphism (Martin and Lutton, 1965), and racemic propylene glycol-l-monostearate shows four different polymorphic crystal forms, whereas optically active L(+)-propylene glycol-l-monostearate is monomorphic (Stauffer, 1967). 

Titanium dioxide [13463-67-7], chemical formula TiO and relative molecular molar mass of 79.8788, occurs in nature in three polymorphic crystal forms anatase, rutile, and brookite. Moreover, under high pressure, the structure of all three polymorphs of titanium dioxide may be converted into that of a-PbO. The main properties of the three polymorphs are... 

N. Shan and M. J. Zaworotko, in Burger s Medicinal Chemistry and Drug Discovery, 7th ed., eds. D. J. Abraham and D. P. Rotella, Polymorphic Crystal Forms and Cocrystals in Drug Delivery (Crystal Engineering), John Wiley Sons, New York, 2010, p. 187. 

Heats of solid-solid transitions must be determined direcdy, either by calorimetry or by measurement of the area under the endothermic peak on a differential-thermal analysis trace. The heats of transition from one polymorphic crystal form to another are listed in order of decreasing temperature, each value having the designation of the form which is stable below the transition temperature. 

In addition, the solid state of the API must not be impacted by the presence of the excipients. The polymorphic crystal form must not change while in contact with the excipients in the dosage unit. Such a change could result in a lower solubility of the new polymorph, reducing the overall bioavailability of the compound. 

Miyamoto and co-workers [37] also studied the effect of orientation on the dielectric a, transition of the a-polymorphic crystal form of poly(vinylidcne fluoride). The relaxation strength of the transition wa.s found to be highest along the direction trf orientation and to decrease down to near zero in the perpendicular direction. With random orientation the relaxation strength b about 4, along the orientation about 22, perpendicularly to the orientation direction near zero. 

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