Effects of HPMC substituent pattern on water up-take, polymer and drug release: An experimental and modelling study
Graphical abstract
Introduction
Due to the high patient compliance, the oral route for administration of pharmaceuticals is often preferred. Additionally, tablets are the most common formulation principle used to gain controlled drug release profiles. These systems are prepared by mixing and tableting the drug of interest, together with excipients (for example polymers) which can improve the processing and adjust the drug release rate (Grassi et al., 2006, Levina and Rajabi-Siahboomi, 2004, Tajarobi et al., 2009b). The drug release rate can be controlled by the release of the polymer matrix, which in that case absorb biological fluids and form an entangled gel. Once a certain hydration at the gel surface is reached, the polymer chain disentangles and erodes from the matrix surface. Simultaneously, the drug is released toward the external environment. One of the most common employed polymer in these systems is hydroxypropyl methycellulose (HPMC), which is a nonionic semi-synthetic polymer characterized by the presence of Methoxyl (MeO) and Hydroxypropoxyl (HPO) groups on the cellulose backbone. Depending on the degree of substitution and molecular weight, several grades of HPMC can be defined (Siepmann and Peppas, 2001). It has been shown that the HPMC molecular weight (Gao et al., 1996, Ju et al., 1995), as well as its degree of substitution (Viridén et al., 2010b, Viridén et al., 2009b), remarkably affects the polymer’s ability to form a coherent gel like structure.
HPMC is known to be a heterogeneous material when it comes to molecular weight, degree of substitution, degree of molar substitution, and distribution of substituents (i) between the HPMC chains, and within the chain on (ii) glucose unit level and (iii) along the cellulose backbone. No HPMC batches of same grade, even when comparing only two HPMC chains, are homogenous, but the degree of heterogeneity can be lower or higher. Viridén (Viridén, 2011) has shown in several studies that the distribution of the substituents along the cellulose backbone, which in this study will be referred to as the substitution pattern, influences the hydration/gel formation and release of drug and polymer (Viridén et al., 2011, Viridén et al., 2010b). This has been explained by hydrophobic interactions between the chains, which results in transient crosslinks between the HPMC chains. For HPMC batches with larger degree of heterogeneity in the substitution pattern these interactions will be even more pronounced (Viridén, 2011). These interactions affect the performance of the gel surrounding the hydrophilic HPMC matrix and make it stiffer (Sarkar, 1979). Moreover, the formation of hydrophobic transient crosslinks lower the polymer disentanglement concentration and the polymer erosion rate (Viridén et al., 2011, Viridén et al., 2010b, Viridén et al., 2009b).
A common approach used to study these systems is based on the macroscopic observation of the drug and polymer released to a dissolution medium, which aims to simulate the gastrointestinal conditions. These results are essential to describe the release and dissolution behaviors of the tablets, however they can only offer a limited insight into the involved mechanisms. To deeper analyze and comprehend, and master the tablets behavior once swallowed, other experiments need to be set up, looking not only at the release into the dissolution medium, but also at the matrix hydration process. Different methodologies have been employed to assess the polymer swelling and erosion behaviors along with the drug release (Huanbutta et al., 2013), ranging from simple and effective gravimetric methods (Barba et al., 2009a) and texture analyses (Cascone et al., 2014, Lamberti et al., 2013) to more complex and nondestructive techniques such as nuclear magnetic resonance microimaging (NMR microimaging or MRI) (Abrahmsen-Alami et al., 2007; Rajabi-Siahboomi et al., 1994; Tajarobi et al., 2009a; Viridén et al., 2011). Furthermore, to better understand the underlying mechanisms, mathematical modeling of the dissolving tablets can be used. By combining simulations and experimental results, one can discriminate between the relative importance of the involved phenomena and thereby speed up the design phase. Several models have been proposed in literature, ranging from the semi-empirical models where the drug release is related to a power function of the time (Peppas, 1985, Peppas and Sahlin, 1989), to the mechanistic models, where mostly the hydration, swelling and drug release are described as diffusion driven processes (Barba et al., 2009b, Caccavo et al., 2015a, Caccavo et al., 2015b, Kaunisto et al., 2010, Kaunisto et al., 2013, Lamberti et al., 2011, Siepmann et al., 1999). The mass transport coupled with the system mechanics is arduous to describe (i.e. a recent simplified (1D) attempt can be found in (Salehi et al., 2016)), since the hydrogel experiences in the dissolution process a glass-rubber transition, which produce the unfolding of the polymeric chains and the liberation of the active species. Most of the time the complex mechanics (large deformation of a non-linear viscoelastic material) is avoided and the deformation is obtained considering local mass balances, which translate in a local variation of volume (i.e. (Caccavo et al., 2015b, Kaunisto et al., 2010)). Therefore the effect of the system mechanics on the mass transport is evaded, considering that the time scale of diffusion is normally way longer than the relaxation process of the structure (the diffusional Deborah number is greater than 1 and the process could be seen as a diffusion in a viscous mixture (Caccavo et al., 2016)).
In this work commercial-like controlled release tablets, made of drug (theophylline), hydrogel forming polymer (HPMC) and excipients (lactose and microcrystalline cellulose) were analyzed via macroscopic dissolution techniques, microscopic nondestructive NMR microimaging analyses (Abrahmsen-Alami et al., 2007), and mathematical modeling (Caccavo et al., 2015b). Two HPMC batches with different heterogeneity of substitution pattern (Viridén et al., 2009b) were used; one batch that is more heterogeneous, referred to as the heterogeneous batch, and another less heterogeneous batch referred to as the homogenous batch (even if it also is heterogeneous). The overall aim of this work was to compare the hydration/gelling and release of polymer and drug from the two formulations with HPMC. To further gain insights in the differences in the release mechanism behind formulations with HPMC with different degree of heterogeneity in the substitution patterns a previously proposed and tuned mechanistic model of hydration, swelling, polymer erosion, and drug release were applied and the predictions compared to the experimental results.
Section snippets
Materials
Two HPMC batches of the same grade (USP 2208) and viscosity grade (100 cps), supplied by Dow Chemical Co., USA and Shin-Etsu Chemical Co. Ltd., Tokyo, Japan, were used. The differences between batch A and B consist mainly in the heterogeneity of Methoxyl (MeO) and Hydroxypropoxyl (HPO) substitution and batch A was more homogeneously substituted than batch B (Viridén et al., 2011, Viridén et al., 2009b). The heterogeneity was determined by analyzing the amount of glucose released after
Mathematical modeling
The tablet dissolution behavior was mathematically modeled using the mixture theory approach coupled with the system deformation previously developed (Caccavo et al., 2015b). In this work two main assumptions were done:
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Lactose was considered as a diffusant with the same transport characteristics as theophylline (hypothesis supported by the very similar self-diffusion coefficients of these molecules in water (Grassi et al., 2001, Ribeiro et al., 2006));
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MCC was combined with the HPMC, forming a
Experimental and calculations of release data
Fig. 5 shows the experimental and calculated masses of the model substance theophylline and HPMC (the heterogeneous batch B and homogenous batch A) in the dissolving tablets. The experiments were performed in two different experimental setups, (i) a USP II dissolution apparatus equipped with an external stationary basket and (ii) a rotating disc with the tablets glued onto the rotating disc. The rotating disc setup fits into the NMR probe and make it possible to simultaneously study the
Conclusions
In this work commercial like tablets containing two batches of release controlling hydroxypropyl methycellulose, HPMC (A and B), with differences in the heterogeneity of the substitution pattern were investigated. The combined approach of experimental (drug and polymer dissolution combined characterization of the hydration process by NMR microimaging) and modeling results proved that formulation A, containing HPMC with less heterogeneous substitution pattern, erode faster than formulation B
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