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

A solid dispersion based on milk-micelle as a drug-carrier for the enhancement of the aqueous solubility of ritonavir

The goal of present investigation was to evaluate the feasibility of formulating a solid-dispersion using milk-micelles as drug-carriers, to enhance the aqueous solubility of ritonavir

Formulation of a drug-phospholipid complex (Naturosome) to enhance the aqueous solubility of standardized extract of Centella asiastica (SCE)

Purpose: To evaluate the enhancement of aqueous solubility of standardized extract of Centella asiastica, a natural drug with known anti- Alzheimer’s activity, by formulating its complex (Naturosome) with a phospholipid - Phospholipon® 90H

Emerging technologies for the non-invasive characterization of physical-mechanical properties of tablets

The density, porosity, breaking force, viscoelastic properties, and the presence or absence of any structural defects or irregularities are important physical-mechanical quality attributes of popular solid dosage forms like tablets. The irregularities associated with these attributes may influence the drug product functionality. Thus, an accurate and efficient characterization of these properties is critical for successful development and manufacturing of a robust tablets. These properties are mainly analyzed and monitored with traditional pharmacopeial and non-pharmacopeial methods. Such methods are associated with several challenges such as lack of spatial resolution, efficiency, or sample-sparing attributes. Recent advances in technology, design, instrumentation, and software have led to the emergence of newer techniques for non-invasive characterization of physical-mechanical properties of tablets. These techniques include near infrared spectroscopy, Raman spectroscopy, X-ray microtomography, nuclear magnetic resonance (NMR) imaging, terahertz pulsed imaging, laser-induced breakdown spectroscopy, and various acoustic- and thermal-based techniques. Such state-of-the-art techniques are currently applied at various stages of development and manufacturing of tablets at industrial scale. Each technique has specific advantages or challenges with respect to operational efficiency and cost, compared to traditional analytical methods. Currently, most of these techniques are used as secondary analytical tools to support the traditional methods in characterizing or monitoring tablet quality attributes. Therefore, further development in the instrumentation and software, and studies on the applications are necessary for their adoption in routine analysis and monitoring of tablet physical-mechanical properties

The enhancement of the aqueous solubility of ritonavir via formulation of a drug-phospholipid complex

Objective: To evaluate the enhancement of aqueous solubility of a poorly water soluble drug ritonavir by forming its complex with a phospholipid (Phospholipon®90H)

Physical properties and solubility studies of Nifedipine-PEG 1450/HPMCAS-HF solid dispersions

Low-order high-energy nifedipine (NIF) solid dispersions (SDs) were generated by melt solvent amorphization with polyethylene glycol (PEG) 1450 and hypromellose acetate succinate (HPMCAS-HF) to increase NIF solubility while achieving acceptable physical stability. HPMCAS-HF was used as a crystallization inhibitor. Individual formulation components, their physical mixtures (PMs), and SDs were characterized by differential scanning calorimetry, powder X-ray diffraction, and Fourier transform infrared spectroscopy (FTIR). NIF solubility and percent crystallinity (PC) were determined at the initial time and after 5 days stored at 25 °C and 60% RH. FTIR indicated that hydrogen bonding was involved with the amorphization process. FTIR showed that NIF:HPMCAS-HF intermolecular interactions were weaker than NIF:PEG 1450 interactions. NIF:PEG 1450 SD solubilities were significantly higher than their PM counterparts (p \u3c 0.0001). The solubilities of NIF:PEG 1450:HPMCAS-HF SDs were significantly higher than their corresponding NIF:PEG 1450 SDs (p \u3c 0.0001-0.043). All the SD solubilities showed a statistically significant decrease (p \u3c 0.0001) after storage for 5 days. SDs PC were statistically lower than their comparable PMs (p \u3c 0.0001). The PCs of SDs with HPMCAS-HF were significantly lower than SDs not containing only PEG 1450. All SDs exhibited a significant increase in PC (p \u3c 0.0001–0.0089) on storage. Thermogravimetric analysis results showed that HPMCAS-HF bound water at higher temperatures than PEG 1450 (p \u3c 0.0001–0.0039). HPMCAS-HF slowed the crystallization process of SDs, although it did not completely inhibit NIF crystal growth

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

Excipient Variability and Its Impact on Dosage Form Functionality

Pharmaceutical excipients are essential components of most modern dosage forms. Although defined as pharmacologically inert, excipients can be thought of as the true enablers of drug product performance. Unintentional variability in the properties of the excipients may be unavoidable, albeit minimizable. The variability may originate from the source, the excipient-manufacturing process, or during the manufacturing of dosage forms. Excipient variability may have a range of influences on their functionality and performance in the dosage form. A better understanding of these influences on the critical quality attributes of the final product is of prime importance. Modern analytical tools provide a significant assistance in characterizing excipient variability to achieve this understanding. The principles and concepts of Quality-by-Design, process analytical technology, and design space, provide a holistic risk-based approach toward manufacture and application of excipients in pharmaceutical formulations. The International Pharmaceutical Excipients Council (IPEC) has developed guidelines for proper selection, use, and evaluation of excipients in pharmaceutical products. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association