Drug Substance Characterization Research Articles

A strategic approach towards mass balance investigations in pharmaceutical drug substance release testing: A peculiar out of specification case study encountered during API manufacture

Mass balance in drug substances release testing is a critical quality attribute in pharmaceutical manufacturing that continues to challenge modern analytical characterization. This specific perspective of mass balance is lacking in literature, and the following work addresses the knowledge gap related to this topic by examining an in-depth case study and detailing the systematic investigation into mass imbalance observed during release testing of a small molecule API. The process followed a logical stepwise progression beginning with most probable causes and expanded to more obscure causes that require a deeper examination of the API in question until the undetected impurity in question was finally identified. The discovered impurity was eventually found to be formed from a unique side reaction that led to the formation of API-related oligomer impurities, which had eluded conventional small molecule release testing strategies. Ultimately, the characterization gap was traced back to deficiency in the LC results of the developed API purity methods. More importantly, this gap provides an ideal opportunity to highlight common oversights and pitfalls encountered in early phase pharmaceutical development especially as it relates to the method development of truly representative chromatography methods in the API characterization. The work reflects on the key lessons learned from the highlighted pitfalls that were encountered in this case study and offers strategic insights to guide and to improve the development workflow for drug substance characterization strategies.

Characterizing the Impact of Spray Dried Particle Morphology on Tablet Dissolution Using Quantitative X-Ray Microscopy

For oral solid dosage forms, disintegration and dissolution properties are closely related to the powders and particles used in their formulation. However, there remains a strong need to characterize the impact of particle structures on tablet compaction and performance. Three-dimensional non-invasive tomographic imaging plays an increasingly essential role in the characterization of drug substances, drug product intermediates, and drug products. It can reveal information hidden at the micro-scale which traditional characterization approaches fail to divulge due to a lack of resolution. In this study, two batches of spray-dried particles (SDP) and two corresponding tablets of an amorphous product, merestinib (LY2801653), were analyzed with 3D X-Ray Microscopy. Artificial intelligence-based image analytics were used to quantify physical properties, which were then correlated with dissolution behavior. The correlation derived from the image-based characterization was validated with conventional laboratory physical property measurements. Quantitative insights obtained from image-analysis including porosity, pore size distribution, surface area and pore connectivity helped to explain the differences in dissolution behavior between the two tablets, with root causes traceable to the microstructure differences in their corresponding SDPs.

Automated small-scale in vitro transfer model as screening tool for the prediction of in vivo-dissolution and precipitation of poorly solubles

Precipitation testing, especially for weakly basic APIs, represents a key parameter in drug substance characterization during early development stages, where the amount of API available is limited. Therefore, it was the aim of this study to develop an automated small-scale in vitro transfer model to characterize the supersaturation and precipitation behavior of two poorly water-soluble drugs. Following automation and scale-down of the standard transfer model, the developed small-scale model was used to assess the impact of gastrointestinal variability, i.e. gastric pH, gastric emptying, and gastrointestinal fluid volumes, on supersaturation and precipitation of two weakly basic model compounds, ketoconazole and a new chemical entity from the research laboratories of Merck KGaA, MSC-A. The experiments revealed that variations in gastrointestinal parameters affected the in vitro behavior of ketoconazole, but not of MSC-A. Elevated gastric pH, as it can result from co-medication with acid-reducing drugs, resulted in lower degrees of supersaturation for both substances. This result is in agreement with the observation that the oral bioavailability of ketoconazole is lowered when proton pump inhibitors are co-administered. The small-scale transfer model presented herein represents a valuable in vitro tool to assess the risk of drug precipitation, additionally covering a broad range of gastrointestinal parameters.

Quantifying Disproportionation in Pharmaceutical Formulations with 35Cl Solid-State NMR.

Reliable methods for the characterization of drug substances are critical for evaluating stability and bioavailability, especially in dosage formulations under varying storage conditions and usage. Such methods must also give information on the molecular identities and structures of drug substances and any potential byproducts of the formulation process, as well as providing a means of quantifying the relative amounts of these substances. For example, active pharmaceutical ingredients (APIs) are often formulated as ionic salts to improve the pharmaceutical properties of dosage forms; however, exposure of such formulations to elevated temperature and/or humidity can trigger the conversion of an ionic salt of an API to a neutral form with different properties, through a process known as disproportionation. It is particularly challenging to identify changes of pharmaceutical components in solid dosage formulations, which are complex heterogeneous mixtures of the API and excipient components (e.g., binders, disintegrants, and lubricants). In this study, we illustrate that ultra-wideline (UW) 35Cl solid-state NMR (SSNMR) can be used to characterize the disproportionation reaction of pioglitazone HCl (PiogHCl) in mixtures with metallic stearate excipients. 35Cl SSNMR can quantitatively detect the amount of PiogHCl in mixed samples within ±1 wt % and measure the degree of PiogHCl disproportionation in formulation samples stressed at high relative humidity and temperature. Unlike other methods used for characterizing disproportionation, our experiments directly probe the Cl- anions in both the intact salt and disproportionation products, revealing all of the chlorine-containing products in the solid-state chemical reaction without interfering signals from the formulation excipients.

Characterization of Drug Substances and Drug Products Using Synchrotron Radiation

Characterization of Drug Substances and Drug Products Using Synchrotron Radiation

Micronization and characterization of drug substances by RESS with supercritical CO2

A RESS (rapid expansion of supercritical solution) process for the preparation of ultra-fine drug particles with no organic solvent has been developed with supercritical CO2. Three drug substances with different solubility in supercritical CO2 were used, and orifice disks and capillary tubes were adapted as an expansion device. The solubilities of drug substances in supercritical CO2 and the effects of various operating parameters on the characteristics of the particles prepared by RESS process were experimentally investigated. The solubility of the drug substance in supercritical CO2 had a major effect on the average diameter of the particle prepared by RESS process, and the particle diameter decreased with the solubility for all the drugs and operating conditions. The particle diameter also decreased with preexpansion temperature and increased with the hole diameter of the orifice nozzle and aspect ratio (L/D) of the capillary tube.

Preformulation Challenges and Advices to Obtain the Bioavailability and Bioequivalence Studies of Pharmaceuticals

A the approval at a Bioavailability/Bioequivalence Studies is a great challenge after a development of Pharmaceuticals. In many instances, the reproach in these studies were correlated successfully to dissimilar drug blood levels caused mainly by impaired absorption. A biopharmaceutical assessment of drug substance is crucial in generic drug product development. An extensive formulation screening has gained increasing attention during the last years after it became evident that decrease the failure bioequivalence risk. Bonding, binding, isomerism and polymorphism (dissolution behavior) are important processes that influence that activity and elimination of many drugs. The identification, characterization and quantification of crystal forms are becoming increasingly important within the pharmaceutical industry. A combination of different physical analytical techniques (as differencial scanning calorimetry, for instance) is usually necessary for this task. Herein a drug categorization according to the biopharmaceutical classification system (BCS) is helpful. The drug solubility in indifferent systems and the permeability assays are very important determinations at characterization of drug substance. In light of the FDA's recent guidances, there is an increased awareness of the potential relevance of dissolution tests but also realizes the need for individualizing the method on a case by case. The evaluation of dissolution profiles changing the media to obtain a pH gradient or simulate fed and fasted conditions may be a tool for predicting bioavailability, and in some cases, replace clinical studies to determine bioequivalence. The permeability assay is considered to be the development gold standard for in vitro prediction of in vivo human intestinal permeability and bioavailability of orally administered drugs (as Caco-2 cells). Although the cost and the ethics aspects bioavailability testing in animals can be an alternative to predict the bioequivalence. The association of well-made characterization of drug, the relevant dissolution profile test and permeability assay gains the maximal information from which factors could have an impact on the oral bioavailability. Preformulation Challenges and Advices to Obtain the Bioavailability and Bioequivalence Studies of Pharmaceuticals

Integrating Polarized Light Microscopy with Vibrational Spectroscopy for Solid-State Characterization of Drug Substances

Integrating Polarized Light Microscopy with Vibrational Spectroscopy for Solid-State Characterization of Drug Substances

Application of thermally stimulated current measurement to the polymorphic characterization of drug substances

The thermal stimulated current measurement was used as an innovative analytical equipment to evaluate the polymorphic properties of terfenadine and Compound A, being developed by Takeda Pharmaceutical Company, Limited. At first, terfenadine, which is known to have polymorphs, was used as a model sample for thermally stimulated current (TSC) analyses. The TSC curves of amorphous and two polymorphs were distinctly different from each other. Therefore, it was considered that TSC measurement could be a useful technique to evaluate the crystalline properties of drug substances. The polymorphs of compound A were difficult to distinguish the characteristics of polymorphs from conventional powder X-ray diffractometry and also differential scanning calorimetry. Forms A and B of compound A were clearly differentiated by the thermal stimulated current properties that were adequate to characterize each form. Thus, it was shown that TSC was extremely useful and powerful tool for identification of complicated polymorphs, which were not distinguished by conventional methods.

Crystal structure elucidation and morphology study of pharmaceuticals in development

The structural characterization of drug substances by X-ray diffraction plays a central role during the development of pharmaceuticals. While powder diffraction is usually employed for the identification of solid phases, the single crystal technique yields detailed structural information, which is needed for purity control, understanding of polymorphism or pseudo-polymorphic behavior, physico-chemical property elucidation and morphology characterization. The structure determination of three active ingredients is discussed in this context. In the first case, we have solved the structure directly from high-resolution powder X-ray data, using the ‘direct-space’ methodology. The polymorphic behavior of the second substance has been rationalized by analyzing the intermolecular interactions and packing motifs of the two modifications in the solid state. For the third compound, we have predicted the morphology from the knowledge of its crystal structure. Solvent mixtures have been used to control the external crystal habit, based upon a detailed analysis of chemical groups emerging from the cleaved crystal surfaces of the calculated morphology.

Microscopy in Pharmaceutical Development

Many different microscopic techniques are utilized in the development of new pharmaceuticals. For that reason, pharmaceutical companies have supported microscopy and microscopists even in the face of retrenchments in many other industries. Microscopy has the following three major uses in pharmaceutical development: 1) solid-state characterization of drug substance; 2) particle size analysis; 3) contaminant identification. Microscopy is also an important component of the study of the biological activity of drugs but that subject will not be discussed here.The analysis of the solid-state properties of new drug candidates is probably the most important and challenging subject of study for pharmaceutical microscopists.1 The primary objective of these studies is identification of the most suitable solid-state form (i.e. polymorph, solvate, hydrate) of the drug substance for development. Polarized light microscopy (PLM), thermal microscopy (TM), infrared microspectroscopy (IR), and Raman microspectroscopy (RM) are all utilized in these studies. Both PLM and TM are used to discover new polymorphs and solvates of the chemical.