Drug-Excipient Compatibility Studies in Formulation Development: Current Trends and Techniques

The safety, efficacy, quality and stability of a formulation are the cornerstones of any new drug development process. In order to consistently maintain these attributes in a finished dosage form, it is important to have a comprehensive understanding of the physico-chemical characteristics of the active pharmaceutical ingredient (API), as well as all other components (e.g. excipients, manufacturing aids, packaging materials) of the drug product. In a new drug development process, a detailed characterization of the API and other formulation components is usually carried out during the preformulation stage. The preformulation stage involves characterization of several aspects of the API including solubility, dissolution, permeability, polymorph/salt screening, stability (solidstate and solution-state), ionization properties, particle size distribution, API-excipient compatibilities etc. [1]. Excipients are ubiquitous to virtually every pharmaceutical formulation, and facilitate the manufacture, stability, administration, delivery of the API, and/or provide other functionalities to the dosage form. Excipients are used to improve processing (e.g. improving powder flow [2, 3], powder compactibility [4-6] etc.), enhance aesthetics (e.g. identification, branding etc. [7]), optimize product performance (e.g. modified drug-release [8-11]), and/or to facilitate patient compliance (e.g. taste masking [12-15]). They may constitute anywhere from 1 to 99 % of the total formulation mass. Due to the intimate contact of the API with one or more excipients in a formulation, there exists a likelihood of physical and/or chemical interactions between them. Any such interactions may result in a negative impact on the physical, stability or performance attributes of the drug product [16, 17]. The choice of excipients is of crucial importance to avoid these negative effects, and to facilitate the development of a robust and an effective formulation [18-20]. Thus, for a rational selection of excipients, screening of excipient-API compatibility is recognized as an important aspect of formulation development. Moreover, the USFDA’s 21st century current Good Manufacturing Practices (cGMP) initiative and International Council on Harmonization (ICH) Q8 guidelines encourage the pharmaceutical manufacturers to apply Quality by Design (QbD) principles in their drug development process [21, 22]. These guidelines include expectations of a clear understanding of any interactions between the formulation components. Moreover, recent advances in various thermal and non-thermal analytical techniques have led to an improved efficiency in the detection, monitoring and prevention of the incompatibilities early in the drug development process [23, 24]. This article aims to provide a brief overview of the nature of drug-excipient incompatibilities; as well as current trends and techniques used to evaluate these compatibilities in formulation development

Influence of the Physicomechanical Properties of Starches on Their Tabletability—A Multivariate Analysis

Purpose The goal of this study was to identify correlations between the physicomechanical properties of different grades of starches with their tabletability. Methods Corn-starch grades (PURE-DENT® B700, PURE-DENT® B810, and PURE-DENT® B830) and pregelatinized corn-starch grades (SPRESS® B818, SPRESS® B820, and SPRESS® B825) were studied for physicomechanical properties, dynamic sorption isotherm, moisture content [MC] (% w/w), dehydration enthalpy (J/g) [ΔHd], and percent crystallinity (%). Tablets (6 mm) were compressed from hand-weighed powders (constant true volume) using Gamlen Tablet Press (Compression pressure-100 MPa; Compression speed- 5mm/s, 50 mm/s). Tablet mechanical strength (TMS) and Heckel parameters were evaluated. Correlation between physicomechanical properties and compression descriptors was evaluated by multivariate method. Results All starches followed Type-III sorption isotherm with open hysteresis loop indicating their large amorphous content. High amorphous content was further confirmed with hollow diffraction peaks of starches in the powder X-ray diffraction studies. Glass transition temperature of all starches was about 101°C. The moisture content and percent crystallinity of all starches was found statistically insignificant. However, PURE-DENT® B830 and SPRESS® B818 showed significantly low ΔHd values. Principle component analysis (PCA) loadings plot calculated with measured physicomechanical properties and TMS showed positive correlation between high Heckel Yield pressure values of plastic and elastic deformation and negative correlation with percent crystallinity, ΔHd, and MC along PC1. These relationships confirmed expected phenomenon in PCA score plots that Starches (PURE-DENT® B830 and SPRESS® B818) with plastic deformation followed by low elastic recovery in the decompression phase shows better tabletability. Furthermore, positive correlation of low ΔHd with TMS might indicate that starches with easy availability of associated water (low ΔHd) might have better tabletability due to water induced material plasticization. Conclusion Out of the six different grades of starches studied PURE-DENT® B830 and SPRESS® B818 showed better tabletability regardless of similar MC and amorphous nature. The better tabletability of these two starches might be attributed to their better plasticization due to loosely bound associated water, and low elastic recovery in the decompression phase

Drug-Excipient Compatibility Studies in Formulation Development: Current Trends and Techniques

The safety, efficacy, quality and stability of a formulation are the cornerstones of any new drug development process. In order to consistently maintain these attributes in a finished dosage form, it is important to have a comprehensive understanding of the physico-chemical characteristics of the active pharmaceutical ingredient (API), as well as all other components (e.g. excipients, manufacturing aids, packaging materials) of the drug product. In a new drug development process, a detailed characterization of the API and other formulation components is usually carried out during the preformulation stage. The preformulation stage involves characterization of several aspects of the API including solubility, dissolution, permeability, polymorph/salt screening, stability (solidstate and solution-state), ionization properties, particle size distribution, API-excipient compatibilities etc. [1]. Excipients are ubiquitous to virtually every pharmaceutical formulation, and facilitate the manufacture, stability, administration, delivery of the API, and/or provide other functionalities to the dosage form. Excipients are used to improve processing (e.g. improving powder flow [2, 3], powder compactibility [4-6] etc.), enhance aesthetics (e.g. identification, branding etc. [7]), optimize product performance (e.g. modified drug-release [8-11]), and/or to facilitate patient compliance (e.g. taste masking [12-15]). They may constitute anywhere from 1 to 99 % of the total formulation mass. Due to the intimate contact of the API with one or more excipients in a formulation, there exists a likelihood of physical and/or chemical interactions between them. Any such interactions may result in a negative impact on the physical, stability or performance attributes of the drug product [16, 17]. The choice of excipients is of crucial importance to avoid these negative effects, and to facilitate the development of a robust and an effective formulation [18-20]. Thus, for a rational selection of excipients, screening of excipient-API compatibility is recognized as an important aspect of formulation development. Moreover, the USFDA’s 21st century current Good Manufacturing Practices (cGMP) initiative and International Council on Harmonization (ICH) Q8 guidelines encourage the pharmaceutical manufacturers to apply Quality by Design (QbD) principles in their drug development process [21, 22]. These guidelines include expectations of a clear understanding of any interactions between the formulation components. Moreover, recent advances in various thermal and non-thermal analytical techniques have led to an improved efficiency in the detection, monitoring and prevention of the incompatibilities early in the drug development process [23, 24]. This article aims to provide a brief overview of the nature of drug-excipient incompatibilities; as well as current trends and techniques used to evaluate these compatibilities in formulation development

Correlation of Structural and Macroscopic Properties of Starches with Their Tabletability Using the SM2 Approach

The effects of PURE-DENT® and SPRESS® starch properties on their compression behavior was characterized using “SM2” approach (structural properties, macroscopic properties, and multivariate analysis). Moisture sorption rate constants, moisture content, amylose and amylopectin degradation enthalpy, percent crystallinity, amylose–amylopectin ratio, and cross-linking degree were used to profile starch structural properties. Particle density, particle size distribution, and Heckel compression descriptors [yield pressure (YP) of plastic deformation, and elastic recovery] were used as macroscopic descriptors. The structural and macroscopic properties were correlated qualitatively [principal component analysis (PCA)] and quantitatively [standard least square regression (SLSR)] with the tablet mechanical strength (TMS). These analyses revealed that the differences correlated with amylose–amylopectin content, particle density, compression mechanisms, and TMS between the starch grades. Univariate analysis proved lacking; however, PCA identified the particle size, moisture content, percent crystallinity, amylose–amylopectin ratio, and YP of plastic deformation and elastic recovery as the main factors influencing the starch TMS. SLSR quantified the positive influence of Fourier transform infrared spectra absorbance ratio at 1022–1003 and YP of the immediate elastic recovery, and the negative contribution of amylopectin content on the TMS. Therefore, starch amylose and amylopectin content, crystallinity, and lower elastic recovery are mainly responsible for better TMS. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sc