Biopharmaceutical Understanding of Excipient Variability on Drug Apparent Solubility Based on Drug Physicochemical Properties. Case Study: Superdisintegrants

Panagiota Zarmpi,Nikoletta Fotaki,Talia Flanagan,James Mann,Elizabeth Meehan

doi:10.1208/s12248-019-0406-y

Panagiota Zarmpi, Nikoletta Fotaki + Show 3 more

Open Access

https://doi.org/10.1208/s12248-019-0406-y

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Abstract

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.

Highlights

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]
The viscosity of a superdisintegrant dispersion with time relates to the degree of crosslinking [37]

Summary

Introduction

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]. 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]. Superdisintegrants are commonly used in immediate release formulations as they promote fast tablet disintegration and improve drug dissolution. Sodium starch glycolate (SSG), croscarmellose sodium (CCS) and crospovidone (CPV) are three commonly used crosslinked superdisintegrants due to their ability to adsorb water and/or swell in low concentrations (typically 2–8% for SSG [5], 0.5– 5% for CCS [6] and 2–5% w/w for CPV [7] in tablet formulations [8]). Swelling refers to the volumetric expansion of excipient particles due to water

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