Palm olein emulsion: a novel vehicle for topical drug delivery of betamethasone 17-valerate

This study aims to investigate the use of palm olein as the oil phase for betamethasone 17-valerate (BV) emulsions. The physicochemical properties of the formulations were characterized. In vitro drug release study was performed with the Hanson Vertical Diffusion Cell System; the samples were quantified with HPLC and the results were compared with commercial products. Optimized emulsion formulations were subjected to stability studies for 3 months at temperatures of 4, 25, and 40°C; the betamethasone 17- valerate content was analyzed using HPLC. The formulations produced mean particle size of 2–4 μm, viscosities of 50–250 mPa.s, and zeta potential between −45 and −68 mV. The rheological analyses showed that the emulsions exhibited pseudoplastic and viscoelastic behavior. The in vitro release of BV from palm olein emulsion through cellulose acetate was 4.5 times higher than that of commercial products and more BV molecules deposited in rat skin. Less than 4% of the drug was degraded in the formulations during the 3-month period when they were subjected to the three different temperatures. These findings indicate that palm olein-in-water emulsion can be an alternative vehicle for topical drug delivery system with superior permeability

Haplophytin B from maclurodendron porteri

An alkaloid from Maclurodendron porteri has been isolated and characterized. Extraction process was conducted by acid-base extraction method followed by column chromatography. The structure was established by nuclear magnetic resonance spectroscopy and mass spectrometry. The compound was identified as haplophytin B which occurs commonly in the Rutaceae family. However, this is the first time this alkaloid was isolated and reported from the species. The compound showed no inhibition against Staphylococus aureus, Pseudomonas aeruginosa, Bacillus cereus and Escherichia coli and no cytotoxic activity against H199 and A549 cell lines

Long-Term Physical (In)Stability of Spray-Dried Amorphous Drugs: Relationship with Glass-Forming Ability and Physicochemical Properties

This study shows the importance of the chosen method for assessing the glass-forming ability (GFA) and glass stability (GS) of a drug compound. Traditionally, GFA and GS are established using in situ melt-quenching in a differential scanning calorimeter. In this study, we included 26 structurally diverse glass-forming drugs (i) to compare the GFA class when the model drugs were produced by spray-drying with that when melt-quenching was used, (ii) to investigate the long-term physical stability of the resulting amorphous solids, and (iii) to investigate the relationship between physicochemical properties and the GFA of spray-dried solids and their long-term physical stability. The spray-dried solids were exposed to dry (<5% RH) and humid (75% RH) conditions for six months at 25 °C. The crystallization of the spray-dried solids under these conditions was monitored using a combination of solid-state characterization techniques including differential scanning calorimetry, Raman spectroscopy, and powder X-ray diffraction. The GFA/GS class assignment for 85% of the model compounds was method-dependent, with significant differences between spray-drying and melt-quenching methods. The long-term physical stability under dry condition of the compounds was predictable from GFA/GS classification and glass transition and crystallization temperatures. However, the stability upon storage at 75% RH could not be predicted from the same data. There was no strong correlation between the physicochemical properties explored and the GFA class or long-term physical stability. However, there was a slight tendency for compounds with a relatively larger molecular weight, higher glass transition temperature, higher crystallization temperature, higher melting point and higher reduced glass transition temperature to have better GFA and better physical stability. In contrast, a high heat of fusion and entropy of fusion seemed to have a negative impact on the GFA and physical stability of our dataset

Molecular Mechanisms Influencing the Performance of Amorphous Formulations for Poorly Water-Soluble Drugs

Crystallisation is a concern for amorphous formulation because it compromises the solubility-enhancing benefit gained from amorphisation. Traditionally, amorphous formulation had been designed primarily based on trial-and-error approach. The success rate for amorphous formulation is unimpressive, due to a poor understanding of the formulation itself, especially with regard to its crystallisation behaviour. Therefore, this thesis aimed to propose a strategic approach for rational design of amorphous formulations, as opposed to the trial-and-error approach. This can be achieved by understanding what drives the crystallisation of amorphous drug, and when and how the amorphous drug crystallises. The information can guide the selection of drugs, excipients and preparation method to achieve amorphous formulations with favourable features. In the first part of the thesis, a systematic protocol was proposed to identify mechanisms via which crystallisation takes place when amorphous drug is dissolved. The stabilisation strategy of supersaturation produced upon dissolution of amorphous drug was then recommended depending on the crystallisation mechanisms. A molecular dynamics (MD) simulations was used to understand drug-polymer interaction during supersaturation. It was revealed that hydrogen bond interaction is an important in stabilising supersaturation. The factors affecting glass-forming ability and long-term physical stability such as preparation method and humidity were then highlighted in the second study. A follow-up study was performed to elucidate the potential complications in using a standardised differential scanning calorimetry to classify promiscuous glass formers into any specific glass-forming ability/glass stability class. In the subsequent study, the effect of physical aging and/or crystallisation of amorphous drugs during storage on supersaturation potential was addressed. It was shown that, minor crystallisation of amorphous drug upon storage did not have a significant impact on the supersaturation potential during dissolution. Instead, the crystallisation pathway of the amorphous drug during dissolution plays a more important role in determining the supersaturation behaviour of some drugs. Finally, the impact of (i) drug loading on physical stability, supersaturation, drug/polymer miscibility, and (ii) the physical aging and/or crystallisation upon storage on supersaturation potential of spray-dried solid dispersions with HPMC-AS were discussed in the last study. It was observed that the effect of drug loading on physical stability and supersaturation, and the effect of physical aging and/or crystallisation during storage on supersaturation potential is highly drug-dependent. Similarly, the stabilisation effect of HPMC-AS varied across model drugs, drug loadings and crystallisation pathways (i.e. in solid or during dissolution). The Flory-Huggins interaction parameter calculated using MD simulations revealed good miscibility between the drugs and HPMC-AS at drug loadings investigated. In the presence of water molecules, various structural organizations of the drugs and HPMC-AS complexes were observed. Taken together, this thesis provides an improved understanding of crystallisation behaviour of amorphous formulations, which is useful to guide a rational design of amorphous formulations

Supersaturation Potential of Amorphous Active Pharmaceutical Ingredients after Long-Term Storage

This study explores the effect of physical aging and/or crystallization on the supersaturation potential and crystallization kinetics of amorphous active pharmaceutical ingredients (APIs). Spray-dried, fully amorphous indapamide, metolazone, glibenclamide, hydrocortisone, hydrochlorothiazide, ketoconazole, and sulfathiazole were used as model APIs. The parameters used to assess the supersaturation potential and crystallization kinetics were the maximum supersaturation concentration (Cmax,app), the area under the curve (AUC), and the crystallization rate constant (k). These were compared for freshly spray-dried and aged/crystallized samples. Aged samples were stored at 75% relative humidity for 168 days (6 months) or until they were completely crystallized, whichever came first. The solid-state changes were monitored with differential scanning calorimetry, Raman spectroscopy, and powder X-ray diffraction. Supersaturation potential and crystallization kinetics were investigated using a tenfold supersaturation ratio compared to the thermodynamic solubility using the µDISS Profiler. The physically aged indapamide and metolazone and the minimally crystallized glibenclamide and hydrocortisone did not show significant differences in their Cmax,app and AUC when compared to the freshly spray-dried samples. Ketoconazole, with a crystalline content of 23%, reduced its Cmax,app and AUC by 50%, with Cmax,app being the same as the crystalline solubility. The AUC of aged metolazone, one of the two compounds that remained completely amorphous after storage, significantly improved as the crystallization kinetics significantly decreased. Glibenclamide improved the most in its supersaturation potential from amorphization. The study also revealed that, besides solid-state crystallization during storage, crystallization during dissolution and its corresponding pathway may significantly compromise the supersaturation potential of fully amorphous APIs

Molecular Mechanisms Influencing the Performance of Amorphous Formulations for Poorly Water-Soluble Drugs

Crystallisation is a concern for amorphous formulation because it compromises the solubility-enhancing benefit gained from amorphisation. Traditionally, amorphous formulation had been designed primarily based on trial-and-error approach. The success rate for amorphous formulation is unimpressive, due to a poor understanding of the formulation itself, especially with regard to its crystallisation behaviour. Therefore, this thesis aimed to propose a strategic approach for rational design of amorphous formulations, as opposed to the trial-and-error approach. This can be achieved by understanding what drives the crystallisation of amorphous drug, and when and how the amorphous drug crystallises. The information can guide the selection of drugs, excipients and preparation method to achieve amorphous formulations with favourable features. In the first part of the thesis, a systematic protocol was proposed to identify mechanisms via which crystallisation takes place when amorphous drug is dissolved. The stabilisation strategy of supersaturation produced upon dissolution of amorphous drug was then recommended depending on the crystallisation mechanisms. A molecular dynamics (MD) simulations was used to understand drug-polymer interaction during supersaturation. It was revealed that hydrogen bond interaction is an important in stabilising supersaturation. The factors affecting glass-forming ability and long-term physical stability such as preparation method and humidity were then highlighted in the second study. A follow-up study was performed to elucidate the potential complications in using a standardised differential scanning calorimetry to classify promiscuous glass formers into any specific glass-forming ability/glass stability class. In the subsequent study, the effect of physical aging and/or crystallisation of amorphous drugs during storage on supersaturation potential was addressed. It was shown that, minor crystallisation of amorphous drug upon storage did not have a significant impact on the supersaturation potential during dissolution. Instead, the crystallisation pathway of the amorphous drug during dissolution plays a more important role in determining the supersaturation behaviour of some drugs. Finally, the impact of (i) drug loading on physical stability, supersaturation, drug/polymer miscibility, and (ii) the physical aging and/or crystallisation upon storage on supersaturation potential of spray-dried solid dispersions with HPMC-AS were discussed in the last study. It was observed that the effect of drug loading on physical stability and supersaturation, and the effect of physical aging and/or crystallisation during storage on supersaturation potential is highly drug-dependent. Similarly, the stabilisation effect of HPMC-AS varied across model drugs, drug loadings and crystallisation pathways (i.e. in solid or during dissolution). The Flory-Huggins interaction parameter calculated using MD simulations revealed good miscibility between the drugs and HPMC-AS at drug loadings investigated. In the presence of water molecules, various structural organizations of the drugs and HPMC-AS complexes were observed. Taken together, this thesis provides an improved understanding of crystallisation behaviour of amorphous formulations, which is useful to guide a rational design of amorphous formulations

The Need for Restructuring the Disordered Science of Amorphous Drug Formulations

The alarming numbers of poorly soluble discovery compounds have centered the efforts towards finding strategies to improve the solubility. One of the attractive approaches to enhance solubility is via amorphization despite the stability issue associated with it. Although the number of amorphous-based research reports has increased tremendously after year 2000, little is known on the current research practice in designing amorphous formulation and how it has changed after the concept of solid dispersion was first introduced decades ago. In this review we try to answer the following questions: What model compounds and excipients have been used in amorphous-based research? How were these two components selected and prepared? What methods have been used to assess the performance of amorphous formulation? What methodology have evolved and/or been standardized since amorphous-based formulation was first introduced and to what extent have we embraced on new methods? Is the extent of research mirrored in the number of marketed amorphous drug products? We have summarized the history and evolution of amorphous formulation and discuss the current status of amorphous formulation-related research practice. We also explore the potential uses of old experimental methods and how they can be used in tandem with computational tools in designing amorphous formulation more efficiently than the traditional trial-and-error approach

Mechanism-based selection of stabilization strategy for amorphous formulations : Insights into crystallization pathways

We developed a step-by-step experimental protocol using differential scanning calorimetry (DSC), dynamic vapour sorption (DVS), polarized light microscopy (PLM) and a small-scale dissolution apparatus (mu DISS Profiler) to investigate the mechanism (solid-to-solid or solution-mediated) by which crystallization of amorphous drugs occurs upon dissolution. This protocol then guided how to stabilize the amorphous formulation. Indapamide, metolazone, glibenclamide and glipizide were selected as model drugs and HPMC (Pharmacoat 606) and PVP (K30) as stabilizing polymers. Spray-dried amorphous indapamide, metolazone and glibenclamide crystallized via solution-mediated nucleation while glipizide suffered from solid-to-solid crystallization. The addition of 0.001%-0.01% (w/v) HPMC into the dissolution medium successfully prevented the crystallization of supersaturated solutions of indapamide and metolazone whereas it only reduced the crystallization rate for glibenclamide. Amorphous solid dispersion (ASD) formulation of glipizide and PVP K30, at a ratio of 50:50% (w/w) reduced but did not completely eliminate the solid-to-solid crystallization of glipizide even though the overall dissolution rate was enhanced both in the absence and presence of HPMC. Raman spectroscopy indicated the formation of a glipizide polymorph in the dissolution medium with higher solubility than the stable polymorph. As a complementary technique, molecular dynamics (MD) simulations of indapamide and glibenclamide with HPMC was performed. It was revealed that hydrogen bonding patterns of the two drugs with HPMC differed significantly, suggesting that hydrogen bonding may play a role in the greater stabilizing effect on supersaturation of indapamide, compared to glibenclamide

Diffusion of betamethasone 17-Valerate from palm olein-based vehicle

The current study aims to produce pharmaceutical formulation using palm olein as the oil phase with betamethasone 17-valerate as the active ingredient and to compare efficacy with that of commercial products. Creams were prepared using Span® 20 and Tween® 20 as surfactants, Carbopol® 940 as thickener, methyl paraben, propyl paraben and chlorocresol as preservatives, propylene glycol as solubilizer and distilled water as aqueous phase. The formulations were characterized, subjected to stability studies for 3 months and degradation of betamethasone 17-valerate in the formulations was analysed using HPLC. Evaluation on drug release with three different viscosities was further performed with Hanson Verticle Diffusion Cell System using cellulose acetate and rat skin as membranes and the samples were quantified with HPLC. The results were compared to that of three commmercially available products. The optimized formulation showed particle size ranging from 3 to 14 µm, viscosity 68.2±1.43 mPa.s, yield stress 36.5± 0.2 Pa, thixotropy 647± 58, pH 5.8± 0.1 and zeta potential -51 ± 11 mV. The creams exhibited pseudoplastic behaviour and found to be thixotropic. Less than 5 % of drug is degraded during the 3-month period when subjected to 3 different temperatures. The drug release rates from palm-olein-in-water emulsions were 4.5 times higher than that of commercial products. In conclusion, these findings proved that the creams produced from palm-olein-in-water emulsion could be a superior alternative vehicle for topical drug delivery system