Drug substance crystallization

Drug Substance Crystal Form (Final Form)... 

There are some useful methods to improve the physical stability of a suspension, such as decreasing the salt concentration, addition of additives to regulate the osmolarity, as well as changes in excipient concentrations, unit operations in the process, origin and synthesis of the drug substance, polymorphic behavior of the drug substance crystals, and other particle characteristics. However, methods based on changes of the particle properties and the surfactants used are the most successful [43],... 

Chemical development Proof of structure and configuration are required as part of the information on chemical development. The methods used at batch release should be validated to guarantee the identity and purity of the substance. It should be established whether a drug produced as a racemate is a true racemate or a conglomerate by investigating physical parameters such as melting point, solubility and crystal properties. The physicochemical properties of the drug substance should be characterized, e.g. crystallinity, polymorphism and rate of dissolution. 

The surface characteristics of a batch of a drug substance may greatly influence its properties in processing (flow, dissolution). Crystals may crystallize in... 

Many dry solid parenteral products, such as the cephalosporins, are prepared by sterile crystallization techniques. Control of the crystallization process to obtain a consistent and uniform crystal form, habit, density, and size distribution is particularly critical for drug substances to be utilized in sterile suspensions. For example, when the crystallization process for sterile ceftazidime pentahydrate was modified to increase the density and reduce the volume of the fill dose, the rate of dissolution increased significantly. 

Methoxypurine was found to crystallize as a hemihydrate from /V,/V -dimethyl formamide, and as a trihydrate from water [63]. Thermal treatment of the trihydrate could be used to obtain the hemihydrate. Zafirlukast was obtained in the form of monohydrate, methanol, and ethanol solvatomorphs, with the drug substance adopting a similar conformation in all three structures [64], In the isostructural methanol and ethanol solvates, the solvent molecules are hydrogen-bonded to two zafirlukast molecules, while in the monohydrate, the water molecules are hydrogen-bonded to three zafirlukast molecules. The structures of the acetone and isopropanol solvatomorphs of brucine have been reported, where the solvent controlled the self-assembly of brucine on the basis of common donor-acceptor properties [65],... 

The structure of the 1 1 methanol solvate of olanzapine has been reported, where pairs of olanzapine molecules form a centrosymmetric dimer by means of C—H—-7t interactions [66]. The solvent molecule was linked to the drug substance through O—H-N, N—H O, and C—interactions. In a new polymorph of the 1 1 dioxane solvatomorph of (+)-pinoresinol, the structure was stabilized by O—H O hydrogen bonds between the compound and the solvent [67], Two new polymorphs of 2-cyano-3-[4-(/Y,jV-diethylamino)-phenyl]prop-2-enethioamide and its acetonitrile solvatomorph have been characterized [68], Although crystallization of the title compound was conducted out of a number of solvents, only the acetonitrile solvatomorph could be formed. 

Owing to the presence of the functional groups in drug substance molecules that promote their efficacious action, the crystallization... 

This chapter provides an introduction to the pharmaceutical sector, and the business of developing new active pharmaceutical ingredients (API). Crystallization is the preferred method of isolating commercial API products because it offers a highly efficient means of purification. The crystallization process is also where the physical properties of the drug substance are defined. These properties can have a significant impact on the formulated product and process, and eventually on the drug release profile in the patient. 

Sustained release from disperse systems such as emulsions and suspensions can be achieved by the adsorption of appropriate mesogenic molecules at the interface. The drug substance, which forms the inner phase or is included in the dispersed phase, cannot pass the liquid ciystals at the interface easily and thus diffuses slowly into the continuous phase and from there into the organism via the site of application. This sustained drug release is especially pronounced in the case of multilamellar liquid crystals at the interface. 

For these reasons, an understanding of the purification conditions and materials used is useful. For example, on using one solvent, impurities could crystallize under the same conditions as the compound of interest, but on using another solvent, the impurities may be left in the solution. Use of a relatively nonvolatile solvent may lead to residual amounts, which are difficult to eliminate. If the drug substance is dissolved in a solvent, filtration is an effective method of removing particulate matter. 

For synthetic drug substances, purification is most often accomplished through crystallization. Preparative chromatography is currently more widely used for biotechnology-derived products than for synthetic drug substances... 

Probably the most important reaction mechanism is the liquid-mediated process (Hi). This is because most drugs, even those not particularly susceptible to hydrolysis, become less stable as the surrounding moisture levels increase. It has been speculated that degradation proceeds via a thin film of moisture on the surface of the drug substance [23], However, studies have indicated that the moisture is concentrated in local regions of molecular disorder, rather than in thin films [24], These regions that are crystal defects or amorphous areas, equate to the reaction nuclei of mechanisms (i) and (ii). 

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