Polymorphism Of Active Pharmaceutical Ingredients Research Articles

Characterization of Ambroxol and Its Hydrochloride Salt Crystals by Bromine K-Edge X-Ray Absorption Near-Edge Structure Spectroscopy and X-Ray Crystal Structure Analysis.

Polymorphic crystals of ambroxol, forms I and II, and form A ambroxol hydrochloride crystals were characterized with bromine K-edge X-ray absorption near-edge structure (XANES) spectroscopy and single-crystal X-ray structure analysis. The XANES spectra had unique shapes depending on the crystal forms. Refined single-crystal structures revealed different interatomic interactions around bromine atoms, such as C-H…Br and N-H…Br hydrogen bonds, Br…O halogen bonds, and N-H…π interactions. Differences in these weak interactions could affect the electronic states of the bromines, resulting in differences in the XANES spectra. The results demonstrated that weak non-conventional interatomic interactions could alter the shape of XANES spectra. Hence, the spectra could be used for evaluating polymorphs of active pharmaceutical ingredients.

Advanced Solid-State NMR Analysis of Two Crystal Forms of Ranitidine Hydrochloride: Detection of 1H-14N Intra-/Intermolecular Correlations.

Understanding the characteristics of crystal polymorphism of active pharmaceutical ingredients and analyzing them with high sensitivity is important for quality of drug products, appropriate characterization strategies, and appropriate screening and selection processes. However, there are few methods to measure intra- and intermolecular correlations in crystals other than X-ray crystallography, for which it is sometimes difficult to obtain suitable single crystals. Recently, solid-state NMR has been recognized as a straightforward method for measuring molecular correlations. In this study, we selected ranitidine hydrochloride, which is known to exist in two forms, 1 and 2, as the model drug and investigated each form using solid-state NMR. In conducting the analysis, rotating the sample tube, which had a 1-mm inner diameter, increased the solid-state NMR resolution at 70 kHz. The 1H-14N dipolar-based heteronuclear multiple quantum coherence (D-HMQC) analysis revealed the intermolecular correlation of Form 1 between the N atom of the nitro group and a proton of the furan moiety, which were closer than those of the intramolecular correlation reported using single X-ray crystal analysis. Thus, 1H-14N D-HMQC analysis could be useful for characterizing intermolecular interaction in ranitidine hydrochloride crystals. In addition, we reassigned the 13C solid-state NMR signals of ranitidine hydrochloride according to the liquid-state and multiple solid-state NMR experiments.

Crystal engineering of a new pharmaceutical polymorph of gallic acid monohydrate: a structural comparative study and chemical computational quantum investigations

Exploiting new polymorphs of active pharmaceutical ingredients (APIs) has a significant role in the development of new processes for the pharmaceutical industry.

Analysis of Cimetidine Crystal Polymorphs by X-ray Absorption Near-Edge Spectroscopy.

Sulfur K-edge X-ray absorption near-edge spectroscopy (XANES) measurements were performed to characterize the crystal polymorphs of the active pharmaceutical ingredients (APIs) containing sulfur atoms. Cimetidine (CIM) was used as a model API. Each crystal form of CIM has its own XANES spectrum, so we can discriminate the crystal form by its spectrum. The analysis of the crystal structure of CIM revealed that the difference in the shape of XANES spectra was ascribable to the difference in the C-S-C bond angle of CIM molecules and the intermolecular hydrogen bonds, such as C-H···S and N-H···S, and S-S interaction. It was found that the peak shape of the XANES spectrum is gentle when the C-S-C bond angle is large, while the peak shape can be steep when the C-S-C bond angle is small. Furthermore, it was found that the peak energy values varied depending on the hydrogen bonds and S-S interaction. By linear combination fitting using XANES spectra, it was possible to quantify the ratio of CIM form A crystal in mixed powders of form A and monohydrate crystals. These results indicate that XANES measurements can be a useful technique to evaluate the crystal polymorphism of APIs containing S atom in pharmaceutical formulation.

Controlled crystallization of metastable polymorphic pharmaceutical: Comparative study of batchwise and continuous tubular crystallizers

The deliberate and reproducible crystallization of metastable polymorphs of active pharmaceutical ingredients (APIs) from solution remains difficult and is still far from trivial. The main challenge is to prevent cross nucleation of the stable form. The traditional cooling experiments in a batch crystallizer cannot repeatably produce aripiprazole (APZ) metastable Form III within selected initial concentrations and cooling rates. The computational fluid dynamics simulations confirmed that fluctuations in temperature and solution concentration in the batch crystallizer would induce the nucleation of stable crystal forms and accelerate solvent-mediated phase transformation. This work presents, for the first time, ultrasonic- and slug-assisted tubular crystallizers for the continuous and controllable preparation of pure metastable crystal Form III of APZ. The ultrasound-assisted air segmented plug flow tubular crystallizer provides an efficient configuration to produce high purity metastable polymorphism pharmaceuticals, which also offers a facile approach for the continuous manufacturing of drug substances.

Topologically directed confocal Raman imaging (TD-CRI): Advanced Raman imaging towards compositional and micromeritic profiling of a commercial tablet components

Particle size distribution (PSD), spatial location and particle cluster size of ingredients, polymorphism, compositional distribution of a pharmaceutical product are few of the most important attributes in establishing the drug release-controlling microstructural and solid state properties that would be used to (re)design or reproduce similar products. There are numerous solid-state techniques available for PSD analysis. Laser diffraction (LD) is mostly used to study PSD of raw materials. However, a constraint of LD is the interference between the active pharmaceutical ingredients (API) and excipients, where it is very challenging to measure API size in a tablet. X-ray powder diffraction (XRPD) is widely employed in establishing the polymorphism of API and excipients. This research examined a commercial osmotic tablet in terms of extracting solid state properties of API and functional excipient by Raman Imaging. Establishing repeatability, reproducibility, and sample representativeness when the samples are non-uniform and inhomogeneous necessitates multiple measurements. In such scenarios, when employing imaging-based techniques, it can be time-consuming and tedious. Advanced statistical methodologies are used to overcome these disadvantages and expedite the characterization process. Overall, this study demonstrates that Raman imaging can be employed as a non-invasive and effective offline method for assessing the solid-state characteristics of API and functional excipients in complex dosage forms like osmotic tablets.

X-ray Absorption Near-Edge Spectroscopy Analysis of Indomethacin in Crystalline Forms and in Amorphous Solid Dispersions.

Chlorine K-edge X-ray absorption near-edge spectroscopy (XANES) measurements were performed to characterize the crystal polymorphs of identical active pharmaceutical ingredients (APIs) containing chloride atoms and their amorphous solid dispersions (ASDs). Indomethacin (IMC), of which three crystal forms (α, β, and γ) have been reported, was used as a model API. The shape of XANES spectra was unique to each IMC crystal. The analysis of the crystal structures of IMC revealed that chlorine atoms of the IMCα form had unique intermolecular interactions and halogen bonds with oxygen atoms, while those of the IMCγ form do not have any notable interactions. This result showed that XANES measurements can detect weak interatomic interactions. The shapes of the ASD spectra were clearly different from those of the crystals, suggesting that the environment around the Cl atom of IMC was different from that of the crystals. A thermal stress test was then performed to study the transformation from the amorphous form to the crystalline form of IMC in the ASD. The powder X-ray diffraction (PXRD) patterns indicated that amorphous IMC transformed into crystals during the thermal stress test. In accordance with the PXRD results, the XANES spectra also transformed from ASD to crystalline form. These results indicate that the IMC transformation could be monitored by XANES measurement. Our findings led us to conclude that XANES measurement is a novel approach for the evaluation of crystal polymorphs of APIs and the crystalline state of APIs in ASDs.

Combining Surface Templating and Confinement for Controlling Pharmaceutical Crystallization.

Poor water solubility is one of the major challenges to the development of oral dosage forms containing active pharmaceutical ingredients (APIs). Polymorphism in APIs leads to crystals with different surface wettabilities and free energies, which can lead to different dissolution properties. Crystal size and habit further contribute to this variability. An important focus in pharmaceutical research has been on controlling the drug form to improve the solubility and thus bioavailability of APIs. In this regard, heterogeneous crystallization on surfaces and crystallization under confinement have become prominent forms of controlling polymorphism and drug crystal size and habits; however there has not been a thorough review into the emerging field of combining these approaches to control crystallization. This tutorial-style review addresses the major advances that have been made in controlling API forms using combined crystallization methods. By designing templates that not only control the surface functionality but also enable confinement of particles within a porous structure, these combined systems have the potential to provide better control over drug polymorph formation and crystal size and habit. This review further provides a perspective on the future of using a combined crystallization approach and suggests that combining surface templating with confinement provides the advantage of both techniques to rationally design systems for API nucleation.

Agomelatine-hydroquinone (1:1) cocrystal: novel polymorphs and their thermodynamic relationship.

Polymorphism of active pharmaceutical ingredients (APIs) is of significance in the pharmaceutical industry because it can affect the quality, efficacy and safety of the final drug product. In this regard, polymorphic behavior of cocrystals is no exception because it can influence the development of cocrystals as potential drug formulations. The current contribution aims to introduce two novel polymorphs [forms (III) and (IV)] of agomelatine-hydroquinone (AGO-HYQ) cocrystal and to describe the thermodynamic relationship between the cocrystal polymorphs. All polymorphs were characterized using powder X-ray diffraction, differential scanning calorimetry, hot-stage microscopy and solubility measurements. In addition, the crystal structure of form (II), which has been previously solved from powder diffraction data [Prohens et al. (2016), Cryst. Growth Des. 16, 1063-1070] and form (III) were determined from the single-crystal X-ray diffraction data. Thermal analysis revealed that AGO-HYQ cocrystal form (III) exhibits a higher melting point and a lower heat of fusion than those of form (II). According to the heat of fusion rule, the polymorphs are enantiotropically related, with form (III) being stable at higher temperatures. Our results also show that the novel form (IV) is the most stable form at ambient conditions and it transforms into form (II) on heating, and therefore, the two polymorphs are enantiotropically related. Furthermore, solubility and van't Hoff plot results suggest that the transition points are approximately 339 K for the pair form (IV)-(II) and 352 K for the pair form (II)-(III).

Transmission Low-Frequency Raman Spectroscopy for Quantification of Crystalline Polymorphs in Pharmaceutical Tablets.

The purpose of this study was to quantify polymorphs of active pharmaceutical ingredients in pharmaceutical tablets using a novel transmission low-frequency Raman spectroscopy method. We developed a novel transmission geometry for low-frequency Raman spectroscopy and compared quantitative ability in transmission mode versus backscattering mode using chemometrics. We prepared two series of tablets, (1) containing different weight-based contents of carbamazepine form III and (2) including different ratios of carbamazepine polymorphs (forms I/III). From the relationship between the contents of carbamazepine form III and partial least-squares (PLS) predictions in the tablets, correlation coefficients in transmission mode ( R2 = 0.98) were found to be higher than in backscattering mode ( R2 = 0.97). The root-mean-square error of cross-validation (RMSECV) of the transmission mode was 3.9 compared to 4.9 for the backscattering mode. The tablets containing a mixture of carbamazepine (I/III) polymorphs were measured by transmission low-frequency Raman spectroscopy, and it was found that the spectral shape changed according to the ratio of polymorphs: the relationship between the actual content and the prediction showed high correlation. These findings indicate that transmission low-frequency Raman spectroscopy possesses the potential to complement existing analytical methods for the quantification of polymorphs.

Polymorphism of Sildenafil: A New Metastable Desolvate

A new anhydrous polymorph of the free base of sildenafil and two solvates (acetonitrile and propanenitrile) have been discovered and fully characterized. The new polymorph can be considered a desolvate of the acetonitrile solvate and is related to the most stable form I by morphotropism. The new polymorph can only be obtained by desolvation of the acetonitrile solvate. Thus, this study is a new example of the importance of this multicomponent family of solid forms in the discovery of new polymorphs of active pharmaceutical ingredients.

Thermodynamic Investigation of Carbamazepine-Saccharin Co-Crystal Polymorphs

Polymorphism in active pharmaceutical ingredients can be regarded as critical for the potential that crystal form can have on the quality, efficacy, and safety of the final drug product. The current contribution aims to characterize thermodynamic interrelationship of a dimorphic co-crystal, FI and FII, involving carbamazepine (CBZ) and saccharin (SAC) molecules. Supramolecular synthesis of CBZ-SAC FI and FII has been performed using thermokinetic methods and systematically characterized by differential scanning calorimetry, powder X-ray diffraction, solubility, and slurry measurements. According to the heat of fusion rule by Burger and Ramberger, FI (ΔHfus = 121.1 J/g; melting point, 172.5°C) and FII (ΔHfus = 110.3 J/g; melting point, 164.7°C) are monotropically related. The solubility and van't Hoff plot results suggest FI stable and FII metastable forms. This study reveals that CBZ-SAC co-crystal phases, FI or FII, could be stable to heat-induced stresses; however, FII converts to FI during solution-mediated transformation.

Mebendazole crystal forms in tablet formulations. An ATR-FTIR/chemometrics approach to polymorph assignment

Structural polymorphism of active pharmaceutical ingredients (API) is a relevant concern for the modern pharmaceutical industry, since different polymorphic forms may display dissimilar properties, critically affecting the performance of the corresponding drug products. Mebendazole (MEB) is a widely used broad spectrum anthelmintic drug of the benzimidazole class, which exhibits structural polymorphism (Forms A–C). Form C, which displays the best pharmaceutical profile, is the recommended one for clinical use. The polymorphs of MEB were prepared and characterized by spectroscopic, calorimetric and microscopic means. The polymorphs were employed to develop a suitable chemometrics-assisted sample display model based on the first two principal components of their ATR-FTIR spectra in the 4000–600cm−1 region. The model was internally and externally validated employing the leave-one-out procedure and an external validation set, respectively. Its suitability for revealing the polymorphic identity of MEB in tablets was successfully assessed analyzing commercial tablets under different physical forms (whole, powdered, dried, sieved and aged). It was concluded that the ATR-FTIR/PCA (principal component analysis) association is a fast, efficient and non-destructive technique for assigning the solid-state forms of MEB in its drug products, with minimum sample pre-treatment.

Quantitative polymorph contaminant analysis in tablets using Raman and near infra-red spectroscopies

The detection and quantification of alternate polymorphs of active pharmaceutical ingredients (APIs), particularly at low concentrations is a key issue for the manufacture and analysis of solid-state formulations. Each polymorph can possess unique physical and chemical properties which in turn can directly affect factors such as solubility and bioavailability. Near infra-red (NIR) and Raman spectroscopies can be used for the rapid characterisation and quantification of polymorphs in solid samples. In this study we have generated a model tablet system with two excipients and a 10% API concentration, where the API is a mixture of the FII and FIII polymorphs of piracetam. Using transmission Raman spectroscopy (TRS) and NIR spectroscopy it was possible to detect FII polymorph contamination in these model tablets with limits of detection (LODs) of 0.6 and 0.7%, respectively, with respect to the total tablet weight (or ∼6–7% of the API content). The TRS method is the superior method because of the speed of analysis (∼6s per sample), better sampling statistics, and because the sharper, more resolved bands in the Raman spectra allowed for easier interpretation of the spectral data. In addition the TRS used here provides facile access to the low frequency wavenumber region for analysis of solid-state lattice modes.

Microfluidic approach to polymorph screening through antisolvent crystallization

Here we present a microfluidic platform comprised of 48 wells to screen for polymorphs of active pharmaceutical ingredients (API) through antisolvent crystallization. API solutions and anti-solvents are precisely metered in various volumetric ratios (range from 50 : 10 to 10 : 50), and mixed via diffusive mixing on-chip. Optical microscopy and Raman spectroscopy were used to analyze the resultant solids. The small volumes (37 nL) and the ability to screen a wide range of supersaturations through diffusive mixing make this platform especially useful for solid form development at discovery and early development stages in pharmaceutical industry. To validate this microfluidic approach, we conducted on-chip antisolvent crystallization using indomethacin. Solvent choice, supersaturation level, and antisolvent-to-solution ratio were found to affect the resulting crystal form of the solids prepared on chip. We modelled the representative time-dependent concentration profiles during the mixing of the antisolvent and API solutions. Combining this analysis with solubility data yielded spatiotemporal supersaturation profiles, which we correlated with solid formation as observed experimentally.

KINETIC CHARACTERIZATION OF DIFFERENT PHENYTOIN POLYMORPHS BY DSC TECHNIQUE

The activation energy variation can be used as a quick measure to differentiate polymorphs of active pharmaceutical ingredients. In this paper diverse phenytoin crystal habits have been obtained through processes of recrystallization in different solvents. Some of these solids differ in melting point by DSC, but are similar in XRD and FT-IR. From the results of melting point, 4 solids are selected by presenting the most dissimilar values. Their activation energy (Ea) is determined by DSC technique, using 3 theoretical isoconversional nonisothermal models and it is found even that 23 Kcal/ mol of difference separate the most extreme values.

A new method for the reproducible generation of polymorphs: two forms of sulindac with very different solubilities

Polymorphism of drugs has been the subject of intense interest in the pharmaceutical industry for over forty years. Although identical in chemical composition, polymorphs differ in bioavailability, solubility, dissolution rate, chemical and physical stability, melting point, colour, filterability, density, flow properties, and many other properties. The difference in solubility is particularly important for pharmaceuticals, as it can affect drug efficacy, bioavailability and safety. Despite significant investment in processes to find all the possible polymorphs of active pharmaceutical ingredients (APIs), new polymorphs can suddenly appear without warning. Polymorphs tend to convert spontaneously from less stable to more stable forms, and, therefore, it is best to discover and characterize the stable form as early as possible. Ideally the most stable polymorph will be found while the drug candidate is still in the discovery process, so that this is the form used for subsequent testing. The most stable polymorph will be the least soluble and solubility may be a limiting factor in the efficacy of the API. Despite the huge importance of polymorphism in the properties of materials, however, there is no method that can produce all the stable polymorphs of a compound, or even one that can provide confidence that the most stable polymorph has been obtained. Here we describe a new method, `potentiometric cycling for polymorph creation (PC)2', which is able to generate the most stable polymorph in aqueous solution. This new method has been applied to sulindac, a non-steroidal anti-inflammatory drug, which also shows promise in anticancer treatment, producing two polymorphs of this API, including a new more stable one. By adjusting the conditions, this method is able to produce either polymorph exclusively.