Purpose: Knowledge on the dissolution behaviour of a drug is critical for efficient and effective product development. As the drug has almost always to be formulated with excipients in the design of a dosage form, it is important to examine the implications of the choice of excipients on the dissolution of the drug, among others, especially in the case of an immediate release dosage form. The objective of this study was to explore the potential of using an ultraviolet (UV) imaging technique to examine the effect of drug-excipient ratio on the initial dissolution of the drug, when formulated with a hydrophilic, water insoluble excipient.
Methods: Acetylsalicylic acid (ASA) was used as the model drug, while microcrystalline cellulose (MCC) was used as the model for a hydrophilic, water insoluble excipient. A nest of three sieves of 180, 125 and 90 μm aperture sizes was used to separate ASA into two size fractions, 90-125 μm and 125-180 μm. A series of drug-excipient binary blends with different ratios were prepared and compacted into 2 mm compacts, and their dissolution profiles captured with a UV imager, which was able to measure the intrinsic dissolution rate (IDR) of ASA. Chemical imaging via Raman spectroscopy was also performed on the compacts to quantify the fraction of drug on the compact surface. Additionally, the enthalpy of interaction between ASA, MCC, and a series of ASA-MCC blends and water was measured with a solution calorimeter.
Results: The 960-1800 cm-1 Raman spectra range was used to build the partial least squares (PLS) regression model for quantification of the surface concentration of ASA used, as prominent ASA peaks reside within. The PLS regression model was applied to the Raman spectral data. The PLS regression modelling of the Raman spectra showed that the surface distribution of ASA and MCC correlated well with the gravimetric ratio of the respective binary blends. Prediction scores generated by PLS regression were used to map the ASA distribution (Figure 1).
The immersion of ASA in water resulted in a positive enthalpy value, which reflects an increasing endothermic reaction with ASA content. Conversely, the introduction of MCC led to a gradual reduction in the enthalpy value, but the overall reaction remained endothermic. Only the 95:5 MCC:ASA blend and pure MCC gave negative enthalpy values, which indicates an exothermic reaction.
A sigmoidal relationship was observed between the concentration of ASA and corrected maximum IDR, regardless of the particle size of ASA used (Figure 2). However, the use of larger particle size fraction resulted in a larger deviation from linearity. At a low drug concentration, a suppression in drug dissolution was observed, but beyond a critical drug-excipient ratio, the concentration of the excipient no longer played a role in affecting drug dissolution rates. Drug particle size was found to affect the critical drug-excipient ratio required to negate the shielding effect exerted by the excipient, such that a higher proportion of was drug required. Based on the Raman surface mapping and solution calorimetry results, it is postulated that the excipient served as a physical barrier, as well as competitor for water required for wetting during initial dissolution, thereby causing a delay in the wetting and dissolution of the drug.
Conclusion: This study attempted to evaluate the shielding effect of a water insoluble excipient, MCC and its impact on the initial dissolution of ASA. The UV imager, which is able to record the real-time release of ASA, enabled the visualization of ASA release upon exposure to water. Additionally, the application of a PLS regression model on the Raman spectra confirmed that the surface distribution of ASA and MCC corresponded closely with their gravimetric proportions. This enabled the analysis of the initial dissolution of compacts prepared with various ASA-MCC proportions. At high MCC concentrations of 75 %, w/w and beyond, it exerted a shielding effect on the release of ASA, which caused a substantial suppression on the maximum IDR achieved, especially in compacts with 95 %, w/w MCC. Additionally, the use of ASA with a larger average particle size fraction at low concentration resulted in further suppression of the maximum IDR. However, once a critical ASA-MCC ratio was achieved, the shielding effect was no longer observed. Two factors were proposed to have led to this observation. Firstly, MCC could act as a physical barrier to hinder the dissolution of ASA, and secondly, MCC could compete for water molecules during in the initial wetting of the compact surface, thereby causing a delay in dissolution which resulted in a decrease in maximum IDR. In view of the observations from this study, researchers and formulators are encouraged to take into consideration the ratio of the drug (s) and excipient(s), especially in the case of low dose immediate release formulations, so that the excipients do not negatively affect the dissolution of the drug(s).