The Development Of Controlled Release Formulation Biology Essay

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Over the years, an enormous number of approaches have been taken to facilitate the development of controlled release formulation. The rationales for such initiatives are to enhance therapeutic advantages while minimizing the adverse effects as well as to improve management of diseases by enhancing compliance and decreasing nursing time.(1) Extended release formulations are usually purported to deliver a drug to a specific site at a specific time frame in a desired release profile.(2) There has always been an aim to achieve zero-order kinetic release as fluctuation of drug concentration in plasma beyond therapeutic level can cause occurrence of side effects.(2) Constant rate release can be achieved by several approaches, including diffusion through a rate-determining barrier, dissolution-controlled release and swelling-controlled release.(2)

Various high molecular weight hydrophilic polymers have been used for synthesis of extended release matrices including hydroxypropyl methylcellulose (HPMC), sodium alginate and polyethylene oxide.(1) However, out of all mentioned, HPMC turns out to be the most frequently used polymer in matrix formulations attributed by its global acceptance, non-ionic nature contributing to high stability, good compaction properties, ability to achieve desired release profiles for various drugs as well as its extensive availability and history of use. Besides that, it is also considered to be non-toxic.(1),(3)

HPMC is a semi-synthetic cellulose ether derivative which consists of a cellulose backbone containing methoxyl and hydroxypropyl groups as substituent.(4) As a non-ionic water soluble polymer, it is considered stable against most of the chemical interaction.(1) The mechanism of drug release from HPMC involves mainly dissolution, diffusion and erosion. Initially, when the matrix tablet comes into contact with a dissolution medium, it is wetted and hydration of the polymer leads to gel formation at the outer layer. The gel layer then grows thicker with time as more water penetrates into the core. This provides a diffusion barrier for drug release. Eventually, the outer layer of the matrix would be fully hydrated and polymer chain would be relaxed. At this point of time, there will be disentanglement of the polymer from the matrix and erosion of the outer layer takes place.(1),(5)

HPMC is available in various grades of viscosity and they are usually selected for use based on drug solubility. Water soluble drugs can dissolve within the gel layer effortlessly and diffuse out from the matrix. Hence, it is essential to maintain matrix integrity to achieve extended release. In such instances, robust gel layer is required to retard drug release. Therefore, HPMC of high viscosity such as HPMC K4M, K15M or K100M is usually chosen for matrix formulation. In contrast, for insoluble drugs, diffusion occurs very slowly across the gel layer formed at the outer surface of the hydrophilic matrix. Hence, polymer with low viscosity such as HPMC K100LV is used to provide adequate erosion to allow drug release.(1)

In all situations for both soluble and insoluble drugs, it is important to have quick polymer hydration followed by rapid gel layer formation to avoid instantaneous tablet disintegration and premature drug release.(1)

In order to achieve extended release from a tablet matrix, certain concentration of polymer is required to be present in the formulation which is sufficient to retard drug release.(4) The minimum concentration required is also known as the percolation threshold.(6) Tajarobi et al. reported that the percolation threshold for HPMC is between 30 and 35%.(7) The matrix was rapidly disintegrated below this concentration but its integrity was maintained at higher concentrations. Despite these findings, it was reported that the percolation threshold depends a lot on drug solubility and there is no absolute value that can be applied to all formulations.(4)

In a study on the release mechanism of drugs from hydrophilic matrices, Sangalli et al. reported that drug release from low viscosity HPMC matrix showed anomalous non-Fickian diffusion. This suggested that despite the occurrence of continuous erosion, the gel layer thickness increased over time which explained the irregular pattern of drug release.(8) This was supported by the work of Asare-Addo et al. At agitation speeds of 5, 10, 15 and 20 dpm, the K100LV matrices also demonstrated anomalous release reflecting non-Fickian behaviour.(9)

There have been quite a number of literatures related to the studies of the effects of HPMC concentration on drug release. Ghimire et al. reported that an increase in HPMC concentration would subsequently increase the gel layer strength and decrease rate of drug release.(6) This was agreed by the work of Mesnukul et al. in which tablets containing lower percentage of HPMC yielded a faster dug release from the matrix compared to those with higher percentage of HPMC content.(10)

The effect of HPMC concentration on erosion rate has also been studied previously. Ghimire et al. examined the erosion behavior of HPMC at concentration below and above the percolation threshold. It was found that tablets made with HPMC below percolation threshold exhibited rapid erosion while those with HPMC above the percolation threshold had a lower erosion rate attributed to stronger gel layer formation and increased resistance towards erosion of the matrix.(6) This was supported by the work of Ugurlu et al. where it has been found that increasing HPMC content in a polymer mixture decreases its rate of erosion.(11)

Texture analyses have been done to obtain the total network penetration of tablets with 25% HPMC after dissolution test at specific time intervals. It was found that the total network penetration decreased with time during dissolution testing. Force required to penetrate swollen tablets also decreased with time indicating that gel strength was reduced as swelling proceeded.(10) This was similar to the findings of Bendgude et al. It was further elaborated in their study that the penetration force increased as soon as the probe made its way through the eroding front and began to penetrate into the swelling part of the matrix.(12)

In a study aimed to examine the effects of substituent heterogeneity on erosion rate, it was found that formulations made of HPMC with longer segments of substituted regions enhanced formation of reversible gel-like structures which subsequently decreased erosion rate of the polymer. This in turn had decreased the rate of drug release and the mechanism of release was dominated by diffusion process.(13)

Dissolution testing is often used as a method to evaluate drug release rate in formulations. It is essential to adhere to the standardized criteria when using dissolution apparatus. The basket apparatus (USP Apparatus I) and the paddle method (USP Apparatus II) have been actively used in the research field. Procedures need to be validated in order to obtain accurate results on drug release profiles. A suitable apparatus and rotational speed should be selected to ensure good mixing of active ingredient and excipients.(14)

In most cases, a mild agitation speed is preferred to allow discriminatory power. This is because results tend to be less discriminating at faster speeds hence yielding a flatter release profile. On the other hand, certain formulations require faster agitation speed to show discrimination as lower speed could cause lack of robustness in results contributed by poor hydrodynamics in the apparatus.(14) According to the implementation guidance, it is important to examine the paddles prior to testing as defects of the paddles can affect the flow dynamics within the vessel hence, yielding aberrant results.(15)

Studies on the effects of paddle speed on drug release rate have been carried out by various researchers in the past few years. Tiwari et al. reported that there was a significant increase in drug release rate when agitation speed was increased from 100 to 150rpm.(1) Besides that, the effect of paddle speed on gravimetric erosion profile of tablets containing 20% and 40% HPMC with lactose was also examined. At the first 60 minutes, the erosion rates for both tablets were similar at the agitation speeds of 50 and 100rpm. However, after 60 minutes, the erosion rates of both tablets at 100rpm were greater than that at 50rpm. Similarity of erosion profiles at both agitation speeds at the first 60 minutes was suggested to be due to rapid dissolution of lactose present as excipient in the tablets.(6)

In another study aimed to develop a discriminating dissolution procedure for two formulations, USP apparatus II was used and the paddles were set to be at a rotational speed of 50±5rpm and 75±5rpm. Tablets were taken out at specific time intervals to quantify percentage of drug release. It was found that the dissolution data obtained at 50rpm was steeper but there was high variability in the results indicating lack of robustness in this method. At 75rpm, the dissolution profile was flatter but with lower variability attributed by the method robustness. When a visual observation was done on dissolution testing at 50rpm, it was found that there was a cone formation at the bottom of the vessel in which drug was trapped in the non-soluble excipient which explained the increase in variability of the data. In contrast, this could not be seen at 75rpm due to rapid turbulence which prevented the cone formation.(14)

In a study reporting the influence of agitation rate on the swelling and erosion properties of HPMC, the ratio of wet weight to initial weight of the tablet served as an indicator of extent of matrix swelling. It was found that for HPMC K100LV, the wet weight decreased with increasing rpm, indicating faster erosion at higher agitation rate. This could be due to an increase in rate of polymer chain detachment from the matrix when paddle speed was increased. In addition, increasing the agitation rate also resulted in a decrease in diffusion layer thickness, which allowed greater mass transport from matrix surface.(5) The findings were similar with the in-vitro and in-vivo erosion studies carried out by Abrahamsson et al. where it was found that erosion rate was significantly increased by elevating paddle speed.(16)

Asare-Addo et al. reported that there was an increase in cumulative percentage drug release over time when agitation speed was increased for all grades of HPMC. However, erosion was quicker in polymers with lower viscosity as they have lower intrinsic water holding capacity.(9),(17) The effect of agitation speed on erosion rate of HPMC K100LV matrices was particularly evident as they are more prone to erosion. The cumulative percentage of drug release from HPMC K100LV at different agitation speeds is shown in Figure 1.This reflects that drug release from HPMC K100LV would be significantly affected by the effects of food and gastrointestinal motility. These effects should be determined to predict drug release at each region of the gastrointestinal tract and prevent undesirable release profiles.(9)

Figure 1: The effect of rate of agitation on drug release from HPMC K100LV matrices(9)

Implementation guidance on standard practice for qualification of dissolution apparatus has been established throughout the years. There are several requirements that should be adhered to in order to achieve reproducibility and accuracy of dissolution data. Hence, there might be a need to verify critical dimensions for parts of the apparatus by making several measurements. It is particularly important to measure the internal dimensions of the dissolution vessel to ensure it meets the standard requirement for dissolution testing. Besides that, it is also important to ensure that the inner surface is smooth and regular. Practically, tactile and visual evaluation is done to detect any defect in the inner surface of the vessels and hence, to determine the suitability of the vessels for routine use.(15)

For a dissolution vessel, it is the inner surface that requires to be monitored regularly. It is rather common for defects to occur in dissolution vessel especially when they are in routine use. They can occur due to handling of the vessels when cleaning and sampling. It was directed in the guideline that the vessel bottom and sides should be checked for any foreign material that might have attached onto it from the previous testing and to ensure that there are no fractures on the vessels. Besides that, the lip of the vessels should be checked as it can be easily damaged when handling. These steps are reported to be significant preventive measures to minimize inaccuracy and data variability.(15) Despite the fact that defects can occur at anytime and there might be a chance that researcher might be unaware of vessel damage, there are limited literatures on the pharmaceutical consequences of these defects.

There are several literatures related to the effects of polymer storage on drug release although they do not necessarily agree to one another. In a study, tablets coated with HPMC were separately stored at 25°C/60%RH, 30°C/60%RH and 40°C/75%RH for up to a year. The release profiles of these tablets were then compared with that of newly manufactured tablets. It was found that there was no significant difference in drug release rates of freshly prepared tablets and those stored in the stress conditions for up to a year. In addition, there were no changes observed in the appearance of the tablets and no significant decrease in their mechanical strength. The review have justified that HPMC is generally very stable attributed to its non-ionic nature and will hardly react with or bind to drug substances.(3)

In a study involving dissolution testing, tablets stored in open containers at 40°C/75%RH for a month were tested against those stored in market package at marketing environment. The result was as shown in Figure 2. It was demonstrated that the storage condition of the tablets affected the dissolution profile.(14)

Figure 2: Dissolution of stressed and unstressed tablets at 75rpm(14)

Besides that, in a study to determine factors affecting drug release from tablets coated with HPMC, it was found that 12%HPMC pellets with no storage showed a higher release rate compared to similar content of HPMC stored at room temperature for four months. It was clarified that this was due to further gradual coalescence of polymer film to form a homogenous continuous film resulting in a more robust matrix during the 4 months period of polymer storage.(18)

The Young and Nelson equations describe the moisture sorption and desorption profile of materials. It has been explained that moisture can be adsorbed from three different locations, namely the monolayer adsorption, externally adsorbed moisture and internally adsorbed moisture.(19)

In a study on the interaction between water and HPMC, it was found that an increase in relative humidity resulted in a subsequent increase in tensile strength of HPMC K4M. It was explained that the distribution of moisture in HPMC should determine the tensile strength of the tablets. Initially adsorbed water molecules formed a monomolecular layer and increased van der Waals forces, smoothing out surface irregularities and reducing void spaces between particles. These effects resulted in an increase in tensile strength. When more water molecules were adsorbed onto the surface, moisture was transferred into the material which led to softening of the tablets. However, area of contact between particles increased under pressure exerted by compaction and more solid bonds were formed contributing to further increase in tensile strength of the tablets. Nokhodchi et al. also reported that decrease in tensile strength due to condensation and multilayer adsorption was not significant. (19)

In another study on effect of adsorbed moisture on the tensile strength of HPMC matrix tablets, Malamataris et al. found that tensile strength of tablets increased initially up to a plateau level and then decreased gradually as moisture content was increased. This could be due to the way moisture was adsorbed onto cellulose derivatives. The attachment of water molecules by strong and weak hydrogen bonding affects the resultant tensile strength of the formulation. It was justified that the eventual decrease in tensile strength was due to attachment of water molecules to already strongly bonded ones by weak dipole interaction which led to weakening of interparticulate bonds within the matrix and softening of the tablets.(20)

The primary aim of this research is to study the effects of polymer storage on gel formation and erosion as well as the correlation of each of these parameters with rate of drug release. Besides that, the research is also aimed to examine the effects of damaged vessels on drug release profiles. In addition, the effects of paddle speed on drug release rate are also to be determined in this study. The polymer of interest is HPMC K100LV since it is most greatly affected by agitation speed and there are limited literatures on this grade of polymer. Paracetamol is used as the active ingredient in the formulation as it has high solubility and good UV absorbance.

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