Impact of Impurities on Crystallization and Product Quality: A Case Study with Paracetamol

A thorough, systematic study into the effect that structurally related impurities have on both the process and product quality during the crystallization of an active pharmaceutical ingredient is presented. The presence of acetanilide and metacetamol influences the crystallization and product quality of paracetamol. Where high concentrations of either impurity were present in the crystallization feed, product recovery decreased by up to 15%. Acetanilide is included in the final product through adsorption onto the particle surface in concentrations up to 0.79 mol%, which can be reduced to acceptable levels through product reslurrying. The presence of metacetamol results in much higher concentrations—up to 6.78 mol% in the final product, of which approximately 1 mol% is incorporated into the crystal lattice, resulting in the perturbation of the unit-cell dimensions. The incidental crystallization and subsequent isolation of metastable Form II paracetamol increased product purity in the presence of a low metacetamol concentration. This metastable product converts to stable paracetamol Form I through reslurrying, offering an efficient metacetamol impurity rejection route. The morphology of the product is modified consistently by both impurities. An elongation of the normal prismatic shape is observed, which in the extreme case of high metacetamol contamination results in the isolation of fine, fragile needles. This problematic morphology is also improved by a reslurrying of the crystallization product to give a more equilateral shape. This systematic study of the influence of acetanilide and metacetamol on the crystallization of paracetamol builds a well-rounded picture of the concomitant impact of impurities on the principal quality attributes of a crystallization product.

Square network based upon the molecular salt of the tetraprotonated photoproduct rtct-tetrakis(pyridin-4-yl)cyclobutane and the sulfate anion

The formation and crystal structure of a hydrated molecular salt that results in a square network is reported. The crystalline solid is based upon the tetraprotonated photoproduct rtct-tetrakis(pyridin-4-yl)cyclobutane (4H- rtct -TPCB)4+ along with two sulfate anions (SO4 2−) and eight waters of hydration, namely, 4,4′,4′′,4′′′-(cyclobutane-1,2,3,4-tetrayl)tetrapyridinium bis(sulfate) octahydrate, C24H24N4 4+·2SO4 2−·8H2O. The fully protonated photoproduct acts as a four-connecting node within the square network by engaging in four charge-assisted N+—H...O hydrogen bonds to the sulfate anion. The observed hydrogen-bonding pattern in this square network is akin to T-silica, which is a metastable form of SiO2. The included water molecules and sulfate anions engage in numerous O—H...O hydrogen bonds to form various hydrogen-bonded ring structures.

Effect of Manual Grinding on Diclofenac Acid Nanocrystals: A Chemico-Physical Investigation

X-ray Powder Diffraction, Fourier Transform Infrared Spectroscopy and Differential Scanning Calorimeter were used to study the effect of the manual grinding in an agate mortar of the diclofenac acid polymorphs HD1 and HD2. In particular, we have tried to highlight how the HD2 form is more sensitive than the HD1 to the grinding process to achieve a nanometric crystal size. HD1 shows no change, while in the case of the HD2, changes in the molecular conformation and the formation of a new metastable form of the polymorph are observed after grinding.

Nucleation control and separation of vanillin polymorphs I and II through the swift cooling crystallization process

Stable form-I and metastable form-II polymorphs of vanillin are identified through morphology and separated in terms of supersaturation ranges from pure aqueous solution without the use of nucleation selecting materials.

The Methods to Crystallize Anhydrous L-Phenylalanine from Methanol-Water Solution

In this paper, the transformation water activity of L-Phenylalanine (L-Phe) in a methanol-water solution at a different temperature was measured by the ternary diagram. The influence of water activity on the transformation temperature and on the transformation rate was investigated. The solubility of the metastable form of different water activities was estimated based on the thermodynamic equilibrium and the results showed that the anhydrous L-Phe can be synthesized at room temperature by decreasing water activity, the transformation rate from monohydrate to anhydrate was enhanced with the increase of water activity. The predicted solubility value is in good agreement with the experimentally obtained. Meanwhile, tailor-made additives were applied into the system as to investigate the transformation behavior of L-Phe. Their mechanism was proposed based on the Langmuir model fitting. The result manifested that the addition of L-Trp/L-His amino acid in the L-Phe solution decelerated the transformation rate. When the concentration of L-Trp amino acid reached 0.7 × 10−4 mol/mL, the transformation behavior of L-Phe can be fully impeded, and the transformation behavior can be partially inhibited with the addition of L-Trp at 313.15 K or with the addition of L-His at 283.15 K/313.15 K.

Stabilisation and Growth of Metastable Form II of Fluconazole in Amorphous Solid Dispersions

The crystallisation of metastable drug polymorphs in polymer matrices has been reported as a successful approach to enhance the solubility of poorly water-soluble drug molecules. This can be achieved using different polymers, drug to polymer ratios and formulation techniques enabling the formation of stable nuclei and subsequent growth of new or metastable drug polymorphs. In this work we elucidated the polymorphism behaviour of a model compound fluconazole (FLU) embedded in solid dispersions with amorphous Soluplus® (SOL) obtained using spray drying and fusion methods. The effect of humidity on the stability of FLU in the obtained dispersions was also evaluated. FLU at a drug content below 40 wt. % stayed amorphous in the dispersions prepared using the fusion method and crystallised exclusively into metastable form II at a drug content above 40 wt. % and 70% relative humidity (RH) conditions. In contrast, a mixture of forms I, II and hydrate of FLU was detected in the spray dried formulations after 14 days of storage at 40 °C/40% RH, with preferential growth of thermodynamically stable form I of FLU. This study highlights the importance of preparation techniques and the drug:polymer ratio in the formulation of amorphous solid dispersions and provides further understanding of the complex crystallisation behaviour of amorphous pharmaceuticals encapsulated in the polymer matrixes.

Solvent-Mediated Polymorphic Transformation of Famoxadone from Form II to Form I in Several Mixed Solvent Systems

This paper discloses six polymorphs of famoxadone obtained from polymorph screening, which were characterized by XRPD, DSC, and SEM. A study of solvent-mediated polymorphic transformation (SMPT) of famoxadone from the metastable Form II to the stable Form I in several mixed solvent systems at the temperature of 30 °C was also conducted. The transformation process was monitored by Process Analytical Technologies. It was confirmed that the Form II to Form I polymorphic transformation is controlled by the Form I growth process. The transformation rate constants depended linearly on the solubility difference value between Form I and Form II. Furthermore, the hydrogen-bond-donation/acceptance ability and dipolar polarizability also had an effect on the rate of solvent-mediated polymorphic transformation.

Antisolvent addition at extreme conditions

Antisolvent addition at high pressure (0.8 GPa) allows crystallization and recovery to ambient pressures of metastable form II paracetamol.