Date Published: February 11, 2020
Publisher: Springer International Publishing
Author(s): Panagiota Zarmpi, Talia Flanagan, Elizabeth Meehan, James Mann, Nikoletta Fotaki.
The presence of different excipient types/brands in solid oral dosage forms may affect product performance and drug bioavailability. Understanding the biopharmaceutical implications of superdisintegrant variability (changes in material properties), variation (changes in excipient amount) and interchangeability (use of different excipient types with the same intended functionality) in oral drug performance would be beneficial for the development of robust final dosage forms. The current study investigated the impact of superdisintegrants (sodium starch glycolate, croscarmellose sodium, crospovidone) on the apparent solubility of drugs with different physicochemical properties (drug ionisation, drug lipophilicity, drug aqueous solubility). Compendial and biorelevant media were used to assess the impact of gastrointestinal conditions on the effects of excipient on drug apparent solubility. For the majority of compounds, changes in drug apparent solubility were not observed in superdisintegrant presence, apart from the cases of highly ionised compounds (significant decrease in drug solubility) and/or compounds that aggregate/precipitate in solution (significant increase in drug solubility). Excipient variability did not greatly affect the impact of excipients on drug apparent solubility. The use of multivariate data analysis identified the biopharmaceutical factors affecting excipient performance. The construction of roadmaps revealed that superdisintegrants may be of low risk for the impact of excipients on oral drug performance based on drug solubility alone; superdisintegrants activity could still be a risk for oral bioavailability due to their effects on tablet disintegration.
Introduction of the Quality by Design (QbD) initiative in pharmaceutical development requires the scientific understanding of the components and processes affecting final product qualities (1). The critical role of excipients in product performance and oral bioavailability is highlighted as presence of excipients in oral formulations may affect the biopharmaceutical profile of drugs with potential implications on drug absorption (2,3). Excipient variability or variation and the use of different excipients with the same intended functionality may further complicate the impact of excipients on oral drug bioavailability (4). The heterogeneous composition in the different regions of the gastrointestinal tract may as well modify the properties and functionality of excipients and presents an additional challenge to assess the impact of excipients on product performance (4).
Superdisintegrant variability and interchangeability present challenges in pharmaceutical development, as the varying excipient physicochemical properties can affect final product quality. Identification of the critical excipient attributes affecting product performance is recommended for the successful control of excipient variability according to the QbD approach. Presence of superdisintegrants (SSG, CCS, CPV) in immediate-release formulations is beneficial for promoting fast tablet disintegration and drug dissolution, but there is a lack of knowledge on the impact of their properties on oral drug performance. In this work, the biopharmaceutical implications of superdisintegrant variability (viscosity type for SSG, particle size distribution for CCS and CPV) on drug apparent solubility were investigated. A data set for the initial risk assessment of the impact of superdisintegrants on oral drug performance was generated and revealed that for the majority of cases, presence of superdisintegrants or superdisintegrant variability did not significantly affect drug apparent solubility. The significant changes in drug solubility at 24 h related to drug physicochemical properties. Reduction in drug apparent solubility was observed for highly ionised drugs and attributed to the adsorption of superdisintegrants around drug particles. Presence of superdisintegrants increased the apparent solubility of poorly soluble drugs containing a neutral aminic group related most probably to drug–excipient interactions or inhibition of drug agglomeration. A clear trend between the excipient effects on drug apparent solubility and drug lipophilicity was not observed. The use of multivariate data analysis and the design of roadmaps allowed the identification of the biopharmaceutical factors affecting the impact of superdisintegrants on drug apparent solubility. Although a limited amount of compounds was included in this study and molecular descriptors were not taken into account for the assessment of the excipient effects on drug solubility, the absence of significant effects on drug solubility in the presence of the studied excipients reveals that, compared to other excipient types (lubricants, binders), superdisintegrants can be considered as of low biopharmaceutical criticality for presenting implications on oral drug absorption.