Hot Melt Extrusion (HME), a novel and potentially disruptive process for manufacturing oral dosage pharmaceutical products, has been explored and studied in recent times, by both industrial and academic investigators, because of its potential of rendering poorly water-soluble active pharmaceutical ingredients (APIs) readily bioavailable to patients through oral dosages. This article presents a brief review of HME from the "elementary steps of polymer processing" perspective: handling of particulate solids, melting, mixing, devolatilization and stripping, pressurization, pumping, as well as dissolution of the API in molten polymeric excipient processed stream. In contrast to traditional polymer processing, the dissolution of the API in the molten excipient during HME is the most important, key, elementary step. The main focus of this article is to discuss the physico-chemical and transport phenomena involved in dissolution and the material, equipment design, and HME process variables which affect it. The main task of the dissolution is to completely dissolve APIs in polymeric melt within the shortest possible residence time, without raising the processed stream melt temperature, and eliminating the possibility of degradation of heat sensitive APIs. We concluded from our work that the dissolution process is a laminar forced convective diffusion process. We will also present results on how to promote the dissolution rate through three categories of variables: process variables (screw speed, feeding rate, barrel temperature,), equipment variables (screw elements and configurations) and material variables (viscosity ratio, solubility parameters and particle sizes of API and excipient particulates). A novel viscometric method for the determination of the solubility of APIs in polymeric melts will also be discussed.

The aim of the presented study was to investigate the possibility of usage of polyethylene oxide polymer (PEO, Polyox® WSR 301, DOW, USA) in the preparation of carbamazepine hot-melt extruded solid dispersions. Hot-melt extrusion (HME) is a simple, solvent free and continuous processing technique used to produce variety of dosage forms. Thermoplastic materials, such as PEO polymers, are required for the process feasibility. Poloxamer 407 (Lutrol® F127, BASF, Germany) was used as a plasticizer to facilitate the HME process, by reducing the processing temperature and lowering the monitored torque. Physico-chemical properties of carbamazepine and polymers, their physical mixtures and dispersions made by melt-mixing or HME were characterized in detail. A hot-melt extruder with one rotating screw was used for the preparation of solid dispersions by HME technique (RCP-0250 Microtruder, Randcastle extrusion systems, USA). Samples were analyzed by differential scanning calorimetry (DSC), thermo-gravimetric analysis (TGA), FT-IR spectroscopy and hot-stage microscopy (HSM) methods. Obtained results indicate that the addition of plasticizer enables preparation of carbamazepine-PEO hot-melt extrudates using a single-screw extruder configuration. It was demonstrated that there is no degradation of CBZ upon heating in the HME processing temperature range (90-110°C). Furthermore, the crystalline form of CBZ was not altered during the HME processing. The presence of CBZ form III crystals, homogeneously dispersed in the hot-melt extrudates, was confirmed. Dispersion of CBZ crystals in the polymers mixtures was visualized using the polarizing HSM technique. Presented study demonstrates the potential of PEO WSR 301 application in the preparation of carbamazepine hot-melt extruded solid dispersions.

The artificial stomach and duodenum (ASD) is a physiologically relevant in vitro dissolution tool that simulates the pH, mixing conditions, fluid composition and fluid flow in the gastric and duodenum compartments[1]. This tool is designed to generate gastric and duodenal concentration profiles to capture dissolution, precipitation and supersaturation phenomena under conditions that simulate the in vivo environment. Duodenal concentration profiles generated from ASD experiments have the potential to provide a rank order prediction of in vivo absorption of compounds as a function of formulation, gastric pH, or gastric emptying time. In this work, we report the IVIVC we established between ASD duodenal concentration profiles generated in our lab, and human in vivo duodenal concentration profiles that were obtained upon oral administration of solution doses of ketoconazole and dipyridamole to healthy volunteers[2]. As an example that demonstrates the application of this tool, we also report on the rank order IVIVC we established between the plasma exposure of dipyridamole[3] and ASD duodenal concentration profiles we generated, under standard and elevated gastric pH conditions. [1]Carino, S. et al. 2006; Relative bioavailability estimation of carbamazepine crystal forms using an artificial stomach-duodenum model. J. Pharm Sci 95(1), 116-125. [2] Psachoulias, D., et al. 2011; Precipitation in and Supersaturation of Contents of the Upper Small Intestine After Administration of Two Weak Bases to Fasted Adults. Pharm. Research, 28(12): 3145-3158 [3] Russell, T. L., et al. 1994; pH-Related Changes in the Absorption of Dipyridamole in the Elderly. Pharm. Research 11 (1): 136-143

Over the years, gene therapy has gained much attention across the field of research. The ability to deliver genes into cells offers the opportunities to treat various human genetic disease which results from mutation or deletion of gene(s). Effective gene delivery is highly dependent on its stability and ability to transfect across cell membrane and interferes with the host DNA. However, DNA is easily susceptible to enzymatic degradation and its large size and highly negatively charged surface are barriers towards successful transfection (1). Therefore, DNA has to be protected from degradation, neutralised and condensed into appropriate size for effective gene delivery. Currently, non-viral vectors are the preferred carrier systems as they are safer, and easier to manufacture. In this research, the use of β and γ-cyclodextrin as non-viral vectors with the incorporation of two different excipients (Pluronic-F127 and folic acid) at different concentrations to stabilise the formulation was investigated. These formulations were characterised in fresh and freeze dried forms. The freeze dried and fresh solutions of DNA were prepared with cyclodextrins (β or γ), folic acid and Pluronic-F127 as excipients in different ratios [(3:3:1, 10:10:1 and 20:10:1) excipient : cyclodextrin : DNA]. The DNA stability in the formulations was tested by determining the stability of DNA against enzymatic degradation (DNase test) using ultraviolet-visible spectroscopy. The degree of DNA inclusion into cyclodextrins was investigated using fluorescence spectroscopy. Fourier Transform Infrared Spectroscopy (FTIR) was employed to study the interaction between DNA and excipients. Scanning Electron Microscope (SEM) was used in observing the surface morphology and uniformity of formed freeze dried particles and thermal behaviour was studied using Differential Scanning Calorimetry (DSC).The formulations were also stored in high humidity (RH=76%) over 5 weeks to access storage stability. In addition, charge measurement was conducted to figure out the transfection efficiency in vivo. It was observed that incorporation of Pluronic-F127 produced the most stable formulations regarding enzymatic degradation, particularly in the freeze dried formulations. These formulations also show high percentage inclusion (>40%). Shift of peaks in FTIR data, appearance of uniform particulate as detected by SEM and changing in the denaturation temperature as demonstrated by DSC data for Pluronic-F127 containing formulations confirms clear interaction between Pluronic-F127 and the cyclodextrin/DNA complex which exhibits positive overall charge. DNA/cyclodextrin formulations containing Pluronic-F127 also showed high stability and protection for the DNA after storage at 76%RH. Overall, it was noted γ-cyclodextrin provide better protection and inclusion compared to β-cyclodextrin. In summary, Pluronic-F127 with β or γ -cyclodextrins is a promising combination to improve stability and delivery of DNA. References 1. Anchordoquy JT, Allison SD, Lorinda M, Girouard G 2001. Physical stabilization of DNA-based therapeutics. Drug Discovery Today. 6:463-470

One "Quality by Design" approach is the focus on the variability of the properties of the active substance. This is crucially important for active substances that are obtained from natural recourses such as herbal plant material and extracts. In this paper we present various strategies for the development of herbal products taking into account especially the natural batch to batch variability (mainly of the dry mass) for tablets that contain a fixed amount of tincture. The following steps of the development have been evaluated for the out come of the physico-chemical properties of the resulting tablets and intermediates: Concentration of the tincture extracted from Echinacea fresh plant, loading of the concentrate onto an inert carrier, the respective wet granulation and drying step, including milling, and the adjuvant excipients for tablet compression step. The responses that were investigated are the mean particle size of the dried and milled granulates, compaction properties and disintegration time of the tablets. Increased particle size has been shown to significant increase of the disintegration time and decrease of the compaction properties. In addition, our results exhibited that the particle size has a great dependency on the ratio of liquid to carrier during the wet granulation process. Thus, the performed strategy of the extracted tincture in correlation to its dry mass and its relation to the amount of carrier used influenced the variability on the respective parameters tested. In order to optimize those parameters, a good strategy has to be carefully chosen.

In this study, mechanical activation (ball- and cryomilling) was successfully applied to obtain co-amorphous mixtures of two BCS class II drugs, simvastatin (SVS) and glipizide (GPZ). This pharmacologically relevant combination of two drugs could produce a promising candidate for formulations intended for combination therapy of metabolic disorders. The co-amorphous SVS-GPZ mixtures (molar ratios 2:1, 1:1 and 1:2) were characterized with respect to their thermal properties, possible molecular interactions, dissolution properties and physical stability, and compared to the behaviour of pure amorphous forms and their physical mixtures. Flory-Huggins interaction parameter predicted the absence of favourable SVS-GPZ interactions and thus immiscibility of the components. Nonetheless, formation of single phase co-amorphous mixtures with mixture ratios of 2:1, 1:1 and 1:2 was detected by differential scanning calorimetry (DSC). The observed single, concentration dependent T_gs were found to be lower than predicted by the Gordon-Taylor equation indicating absence of intermolecular interactions between the two drugs which was verified by Fourier transform infrared spectroscopy (FTIR) spectral data analysis. By formation of co-amorphous single-phase mixtures only the dissolution rate of GPZ could be improved. The co-amorphous mixtures showed improved storage stability compared to the pure amorphous forms and the amorphous physical mixtures. It was concluded that this was attributable to the molecular level mixing of SVS with GPZ upon milling and GPZ is acting as an anti-plasticizer in these mixtures.

Co-amorphous drug systems have recently shown to be a potential new strategy in stabilizing the amorphous state of a drug and increasing its apparent dissolution. The improved properties of these systems, when compared to the single amorphous drug, were attributed to molecular interactions between the drug and its co-amorphous partner. In this regard, vibrational spectroscopy presents a useful tool to analyse these interactions because changes in the molecular arrangement may be reflected in shifts in the vibrations of functional groups involved in such interactions, e.g. hydrogen bonding. However, even with single amorphous compounds this analysis can be challenging because changes are often minor or get lost in the complexity of the spectra. In case of materials with more than one compound, this becomes even more complicated. The purpose of this study was to investigate the molecular near range order of the co-amorphous blend of naproxen (NAP) and indomethacin (IND) (1:1 molar ratio) using quantum mechanical calculations together with FT-infrared (IR) spectroscopy. Initially, both drug molecules were optimized as monomer, homodimer and heterodimer using density functional theory. In a second step the respective IR spectra were calculated. Comparison of the calculated and experimental spectra of the individual drugs revealed that both molecules exist as homodimers in their respective amorphous state. A detailed analysis of the theoretical heterodimer and experimental co-amorphous spectra revealed that the changes of vibrational modes were similar in both, when compared to the single amorphous or homodimer spectra. This indicates that both drugs form a heterodimer when prepared as a co-amorphous 1:1 molar blend.

One of the greatest challenges facing the pharmaceutical industry is the design and development of suitable delivery systems to overcome poor dissolution profile for insoluble drugs. Different formulation approaches including particulate systems, pH alterations and co solvents have been investigated in an attempt to determine the critical formulation parameters to improve dissolution and solubility of poorly soluble drugs. The present study aims to investigate formulation development of solid dispersions for model poorly soluble drug, paracetamol with an overall objective of deciphering drug release mechanisms. Solid dispersions of paracetamol in polyethylene glycol 8000 as a hydrophilic carrier showed that dissolution rate was significantly increased when compared to polymer free formulations and was controlled by the rate of polymer dissolution. The study also showed that polymer to drug ratio was another key factor affecting drug release kinetics. In addition, stability studies were performed according to ICH guidelines. Hyper-differential scanning calorimetry (Hyer-DSC), fourier transform infrared spectroscopy (FTIR), drug content and thermogravimetric analysis (TGA) were carried out as part of the quality assessment criterion during stability studies. The results concluded that solid dispersions of paracetamol were stable at room conditions.

The application of X-ray powder diffraction (XRPD) combined with pair-wise distribution function (PDF) in detecting miscibility in amorphous polymer systems has been demonstrated.1 Here, a matching PDF between linearly combined (theoretical) PDF for the pure components and measured PDF suggests that the sample is immiscible; dissimilar PDF profiles indicates the system is miscible. However, interpretation of overlaid PDF data can be subjective. The objective of this study is to demonstrate the feasibility of using principal component analysis (PCA) to analyse XRPD-PDF data to detect miscibility in freeze dried amorphous-amorphous systems. Polyvinylpyrrolidone 30k (PVP30), PVP 90k (PVP90), dextran 10k (DEX10), polyvinyl alcohol (PVA) and trehalose dihydrate (TREH) were used as received. Formulations (A) PVP30-DEX10, (B) PVP30-PVA and (C) PVP90-TREH at various ratios were prepared and freeze dried below the collapse temperature. All samples were characterised and analysed using XRPD, PDF, PCA and validated by differential scanning calorimetry. Previously it has been reported that PVP30-DEX10 is immiscible, while PVP30-PVA and PVP90-TREH are miscible systems. In our PDF plots, subtle characteristic changes could be observed between theoretical and measured data. However interpreting PDF changes was subjective and is limited to one-to-one comparison. When XRPD-PDF analysis is combined with PCA, comparison of multiple PDF profiles with superior clarity on the subtle changes was achieved. Overall, PCA plots effectively distinguished systems that are immiscible or miscible. XRPD-PDF analysis combined with PCA can be used as an alternative tool to screen and detect miscibility of binary amorphous formulations.

In order to obtain a good in vivo-in vitro correlation (IVIVC), biorelevant dissolution media (BDM) are used to simulate the properties of gastric fluid. The viscosities of currently used BDM are close to that of water and are therefore not physiologically relevant. The dissolution rate of a drug compound is influenced strongly by the viscosity of the dissolution medium, and a physiologically relevant viscosity of the medium is therefore important to obtain a good IVIVC. In the present study it was desired to create BDM with viscosities similar to human gastric fluid. Human gastric fluid was collected from 7 volunteers and the rheological behaviour was investigated and the apparent viscosities determined using cone and plate geometry. The apparent viscosity was determined to be 0.0015 - 0.012 Pa∙s measured at a shear rate of ~10 – 1000 sec^-1. The human gastric fluid displayed a predominant elastic behaviour at low oscillation torques (~0.001 – 1 μN∙m). A fasted-state simulated gastric fluid (FaSSGF) was chosen as a starting point for the creation of viscous BDM. FaSSGF was prepared with different amounts of viscosity enhancer added. A natural viscosity enhancer used for the study was negatively charged porcine gastric mucin (PGM). The other viscosity enhancer used was the semi-synthetic neutral polymer hydroxypropyl methylcellulose (HPMC). FaSSGF containing HPMC displayed an elastic behaviour whereas FaSSGF containing mucin displayed a viscous behaviour. It was found that the addition of 0.2 – 0.6 % HPMC or 1 – 5 % mucin produced media with a viscosity range similar to that of human gastric aspirates. HPMC was the preferred viscosity enhancer due to the rheological behaviour, whereas PGM was preferred due to the natural charge.