The development of PVP-based solid dispersions using hot melt extrusion for the preparation of immediate release formulations

Bioavailability and clinical effectiveness of a poorly soluble drug can be highly affected by its formulation design. In this respect, research on solid dispersion of hydrophilic carrier has commenced a decade ago to resolve the problem of poorly soluble drug. However, the availability of solid dispersion is commercially limited due to the concerns of its physical instability, unpredictability and inconsistency formulation performance. This is attributed to the lack of fundamental understanding on the processing method, physicochemical properties of the obtained solid dispersion. Therefore, better understanding on the processing methods and factors underlying the performance of solid dispersion may be required to maximize the use of solid dispersion. Hot melt extrusion (HME) method was introduced in formulating solid dispersion. The use of this production method offers many advantages such as environmental friendly, cost sparing and readily scalable production as compared to conventional methods. On the other hand, the hydrophilic polyvinylpyrrolidone (PVP) polymer with its good stabilising ability in the solid dispersion is less applied in HME process due to its possible degradation at high temperature. However, rejection on the use of PVP without thorough understanding of its potential might lead to underuse of this polymer in HME solid dispersion. This project explores the feasibility of using PVP and its derivative in HME manufacturing method. It offers an in-depth study on the hot melt processing, physical stability and dissolution behaviour of HME PVP-based solid dispersion. Factors affecting the production of fully amorphous solid dispersion and its physical stability are discussed, taking into account the influence of the composition and characteristic of the drug, drug-polymer interaction and the molecular weight of the polymer. In parallel, HME poorly soluble drug in PVP based solid dispersion were produced and investigated for their dissolution performances in order to understand the mechanism underlying the dissolution process of the HME PVP-based solid dispersion system

An investigation into the factors governing the degree of dissolution enhancement of solid dispersion for poorly soluble drugs

Solid dispersion (SD) formulation has attracted muchattention due to its potential in enhancing dissolutionperformances of poorly soluble active pharmaceutical ingredients(API). Recently, a review on dissolution performances of SDsclassifies the improvement into 3 categories, where 82 % of thestudies showed improved bioavailability, 8 % showed reducedbioavailability and 10 % revealed similar bioavailability ascompared to pure APIs. This indicates the inconsistent degrees ofdissolution improvement of poorly soluble APIs in SD. Althougha few factors related to the choice of carriers have been suggestedto contribute to the dissolution improvement, however, theunderlying factor determining the discrepancy in the degree ofdissolution improvement remains in vague. It is hypothesizedthat the API contributes to the degree of dissolutionimprovement of SD. Hence, the factor of amorphous solubilityadvantage of API which leads to the different degrees ofdissolution enhancement of SD is investigated in this research.Polyvinylpyrrolidone vinyl acetate (PVPVA)-based SD isprepared with three poorly soluble APIs. Physicochemicalproperties of SD were characterized using infrared spectroscopy,differential scanning calorimetry (DSC) and X-ray powderdiffraction. The dissolution efficiency of each SD was calculatedand compared to physical mixture and pure API. Theoreticalamorphous solubility advantage for each API was calculatedusing the thermal properties obtained from DSC. The calculatedvalues were found to be correlating well with the dissolutionenhancement of the respective SDs. Hence, this theoreticalapproach can be utilized as an initial screening tool of APIcandidates in SD formulation during early pharmaceuticaldevelopment

An investigation into the influence of drug-polymer interactions on the miscibility, processability and structure of polyvinylpyrrolidone-based hot melt extrusion formulations

While hot melt extrusion is now established within the pharmaceutical industry, the prediction of miscibility, processability and structural stability remains a pertinent issue, including the issue of whether molecular interaction is necessary for suitable performance. Here we integrate the use of theoretical and experimental drug–polymer interaction assessment with determination of processability and structure of dispersions in two polyvinylpyrrolidone-based polymers (PVP and PVP vinyl acetate, PVPVA). Caffeine and paracetamol were chosen as model drugs on the basis of their differing hydrogen bonding potential with PVP. Solubility parameter and interaction parameter calculations predicted a greater miscibility for paracetamol, while ATR-FTIR confirmed the hydrogen bonding propensity of the paracetamol with both polymers, with little interaction detected for caffeine. PVP was found to exhibit greater interaction and miscibility with paracetamol than did PVPVA. It was noted that lower processing temperatures (circa 40 °C below the Tg of the polymer alone and Tm of the crystalline drug) and higher drug loadings with associated molecular dispersion up to 50% w/w were possible for the paracetamol dispersions, although molecular dispersion with the non-interactive caffeine was noted at loadings up to 20% w./w. A lower processing temperature was also noted for caffeine-loaded systems despite the absence of detectable interactions. The study has therefore indicated that theoretical and experimental detection of miscibility and drug–polymer interactions may lead to insights into product processing and extrudate structure, with direct molecular interaction representing a helpful but not essential aspect of drug–polymer combination prediction

The Interplay between Drug and Sorbitol Contents Determines the Mechanical and Swelling Properties of Potential Rice Starch Films for Buccal Drug Delivery

Rice starch is a promising biomaterial for thin film development in buccal drug delivery, but the plasticisation and antiplasticisation phenomena from both plasticisers and drugs on the performance of rice starch films are not well understood. This study aims to elucidate the competing effects of sorbitol (plasticiser) and drug (antiplasticiser) on the physicochemical characteristics of rice starch films containing low paracetamol content. Rice starch films were prepared with different sorbitol (10, 20 and 30% w/w) and paracetamol contents (0, 1 and 2% w/w) using the film casting method and were characterised especially for drug release, swelling and mechanical properties. Sorbitol showed a typical plasticising effect on the control rice starch films by increasing film flexibility and by reducing swelling behaviour. The presence of drugs, however, modified both the mechanical and swelling properties by exerting an antiplasticisation effect. This antiplasticisation action was found to be significant at a low sorbitol level or a high drug content. FTIR investigations supported the antiplasticisation action of paracetamol through the disturbance of sorbitol–starch interactions. Despite this difference, an immediate drug release was generally obtained. This study highlights the interplay between plasticiser and drug in influencing the mechanical and swelling characteristics of rice starch films at varying concentrations

The Interplay between Drug and Sorbitol Contents Determines the Mechanical and Swelling Properties of Potential Rice Starch Films for Buccal Drug Delivery

Rice starch is a promising biomaterial for thin film development in buccal drug delivery, but the plasticisation and antiplasticisation phenomena from both plasticisers and drugs on the performance of rice starch films are not well understood. This study aims to elucidate the competing effects of sorbitol (plasticiser) and drug (antiplasticiser) on the physicochemical characteristics of rice starch films containing low paracetamol content. Rice starch films were prepared with different sorbitol (10, 20 and 30% w/w) and paracetamol contents (0, 1 and 2% w/w) using the film casting method and were characterised especially for drug release, swelling and mechanical properties. Sorbitol showed a typical plasticising effect on the control rice starch films by increasing film flexibility and by reducing swelling behaviour. The presence of drugs, however, modified both the mechanical and swelling properties by exerting an antiplasticisation effect. This antiplasticisation action was found to be significant at a low sorbitol level or a high drug content. FTIR investigations supported the antiplasticisation action of paracetamol through the disturbance of sorbitol–starch interactions. Despite this difference, an immediate drug release was generally obtained. This study highlights the interplay between plasticiser and drug in influencing the mechanical and swelling characteristics of rice starch films at varying concentrations

The characterization and dissolution performances of spray dried solid dispersion of ketoprofen in hydrophilic carriers

Solid dispersion is one of the most promising strategies to improve oral bioavailability of poorly soluble API. However, there are inconsistent dissolution performances of solid dispersion reported which entails further investigation. In this study, solid dispersions of ketoprofen in three hydrophilic carriers, i.e. PVP K30, PVPVA 6:4 and PVA were prepared and characterized. Physical characterization of the physical mixture of ketoprofen and carriers shows certain extent of amorphization of the API. This result is coinciding to evaluation of drug–polymer interaction using ATR-FTIR whereby higher amorphization was seen in samples with higher drug–polymer interaction. XRPD scanning confirms that fully amorphous solid dispersion was obtained for SD KTP PVP K30 and PVPVA system whereas partially crystalline system was obtained for SD KTP PVA. Interestingly, dissolution profiles of the solid dispersion had shown that degree of amorphization of KTP was not directly proportional to the dissolution rate enhancement of the solid dispersion system. Thus, it is concluded that complete amorphization does not guarantee dissolution enhancement of an amorphous solid dispersion system

Statistical Analysis of Green Laboratory Practice Survey: Conservation on Non-Distilled Water from Distillation Process

The water crisis is identified as the most serious global risk for the coming decade. Distilled water is one of the on-demand elements in academic laboratories; however, water scarcity may eventually affect the education sector, necessitating the implementation of new policies. Human behavior, awareness, knowledge, and opinion is having an impact on water management; accordingly, a questionnaire was purposely designed and validated to assess these variables in a Malaysian public university regarding the use of non-distilled water produced by the distillation process. An exploratory factor analysis yielded four factors: “concept of green laboratory and water”, “usage of non-distilled water”, “knowledge about water distillation”, and “behavior related to water conservation”. Using the Mann–Whitney U test to compare laboratory and non-laboratory users’ responses, the variables “Knowledge”, “Behavior”, and “Opinion” revealed statistically significant differences, with laboratory users scoring higher in all four variables. Employing the Kruskal–Wallis H test in an occupation-based comparison among laboratory users, and with an additional variable “Practice”, showed that “Lecturer” has the highest mean rank for “Awareness”, “Behavior”, and “Opinion”, while “Laboratory Assistant” has the highest mean rank for “Knowledge”. This study provides a rationale analysis for future insights to educate faculty members about the reuse of non-distilled water sustainably

Liquid and Solid Self-Emulsifying Drug Delivery Systems (SEDDs) as Carriers for the Oral Delivery of Azithromycin: Optimization, In Vitro Characterization and Stability Assessment

Azithromycin (AZM) is a macrolide antibiotic used for the treatment of various bacterial infections. The drug is known to have low oral bioavailability (37%) which may be attributed to its relatively high molecular weight, low solubility, dissolution rate, and incomplete intestinal absorption. To overcome these drawbacks, liquid (L) and solid (S) self-emulsifying drug delivery systems (SEDDs) of AZM were developed and optimized. Eight different pseudo-ternary diagrams were constructed based on the drug solubility and the emulsification studies in various SEDDs excipients at different surfactant to co-surfactant (Smix) ratios. Droplet size (DS) < 150 nm, dispersity (Đ) ≤ 0.7, and transmittance (T)% > 85 in three diluents of distilled water (DW), 0.1 mM HCl, and simulated intestinal fluids (SIF) were considered as the selection criteria. The final formulations of L-SEDDs (L-F1(H)), and S-SEDDs (S-F1(H)) were able to meet the selection requirements. Both formulations were proven to be cytocompatible and able to open up the cellular epithelial tight junctions (TJ). The drug dissolution studies showed that after 5 min > 90% and 52.22% of the AZM was released from liquid and solid SEDDs formulations in DW, respectively, compared to 11.27% of the pure AZM, suggesting the developed SEDDs may enhance the oral delivery of the drug. The formulations were stable at refrigerator storage conditions