Stabilizing vaccines via drying: Quality by design considerations.

Pandemics and epidemics are continually challenging human beings' health and imposing major stresses on the societies particularly over the last few decades, when their frequency has increased significantly. Protecting humans from multiple diseases is best achieved through vaccination. However, vaccines thermal instability has always been a hurdle in their widespread application, especially in less developed countries. Furthermore, insufficient vaccine processing capacity is also a major challenge for global vaccination programs. Continuous drying of vaccine formulations is one of the potential solutions to these challenges. This review highlights the challenges on implementing the continuous drying techniques for drying vaccines. The conventional drying methods, emerging technologies and their adaptation by biopharmaceutical industry are investigated considering the patented technologies for drying of vaccines. Moreover, the current progress in applying Quality by Design (QbD) in each of the drying techniques considering the critical quality attributes (CQAs), critical process parameters (CPPs) are comprehensively reviewed. An expert advice is presented on the required actions to be taken within the biopharmaceutical industry to move towards continuous stabilization of vaccines in the realm of QbD.

Formation of Ciprofloxacin-Isonicotinic Acid Cocrystal Using Mechanochemical Synthesis Routes-An Investigation into Critical Process Parameters.

The mechanochemical synthesis of cocrystals has been introduced as a promising approach of formulating poorly water-soluble active pharmaceutical ingredients (APIs). In this study, hot-melt extrusion (HME) as a continuous process and grinding and ball milling as batch processes were employed to explore the feasibility of cocrystallization. Ciprofloxacin (CIP) and isonicotinic acid (INCA) were selected as the model API and coformer. CIP-INCA cocrystal was produced in all techniques. It was revealed that higher cocrystal content could be achieved at longer durations of grinding and ball milling. However, milling for more than 10 min led to increased co-amorphous content instead of cocrystal. A design of experiment (DoE) approach was used for deciphering the complex correlation of screw configuration, screw speed, and temperature as HME process parameters and their respective effect on final relative cocrystal yield. Statistical analysis showed that screw configuration, temperature, and their interaction were the most critical factors affecting cocrystallization. Interestingly, screw speed had minimal impact on the relative cocrystallization yield. Cocrystallization led to increased dissolution rate of CIP in phosphate buffer up to 2.5-fold. Overall, this study shed a light on the potential of mechanochemical synthesis techniques with special focus on HME as a continuous process for producing cocrystals.

Amorphous solid dispersion of ibuprofen: A comparative study on the effect of solution based techniques.

Amorphous solid dispersion (ASD) is one of the most promising strategies for improving the solubility of active pharmaceutical ingredients (APIs) with low aqueous solubility. Solvent-based techniques such as electrospinning (ES), spray-drying (SD) and rotary evaporation (RE), have all previously been shown to be effective techniques for formulating ASDs. To date however, the effect of these processing techniques on the physicochemical properties and ASD homogeneity or "quality of ASD" produced remains largely unexplored. This work uses ibuprofen (IBU) as a model BCS class II API with two cellulosic excipients, HPMCAS and HPMCP-HP55 to produce ASDs by employing ES, SD and RE processing techniques. The physicochemical, morphological and dissolution properties of each sample were evaluated and the ASD forming strengths of each of the polymers were assessed using Differential Scanning Calorimetry (DSC). Principal |Component Analysis (PCA) of Raman spectra of crystalline and amorphous IBU was employed for qualitative analysis of ASD homogeneity and subsequent ASD stability during long-term storage. Results show that while ASD formation is predominantly dependent on API:excipient ratio, the ASD homogeneity is highly dependent on processing technique. Dissolution studies show that electrospun samples had the highest API release rate due to their fibrous morphology and higher specific surface area. However, these samples were the least homogenous of all ASDs produced thereby potentially influencing sample stability during long term storage. In addition, the higher melting point depression, higher Tg, and increased abundance of functional groups suitable for hydrogen bonding, show HPMCAS to be a significantly better ASD co-former when compared with HPMCP-HP55.

Impact of polymeric excipient on cocrystal formation via hot-melt extrusion and subsequent downstream processing.

Pharmaceutical cocrystals have gained increasing interest due to their potential to modify the physicochemical properties of drugs. Herein, a 1:1 cocrystal of ibuprofen (IBU) as a BCS class II active pharmaceutical ingredient (API) and nicotinamide as coformer was produced using a hot-melt extrusion (HME) process. The effect of process parameters such as barrel temperature and screw speed were studied. It was shown that the addition of polymeric excipient such as soluplus (Sol) decreases the cocrystallization temperature by enhancing the interaction between API and coformer. In order to study the effect of cocrystallization on the tableting properties of IBU-NIC cocrystal, 5 different formulations of pure IBU, IBU-NIC cocrystal, IBU-NIC physical mixture, IBU-NIC-Sol physical mixture and IBU-NIC-Sol cocrystal were tableted by a compaction simulator. Tabletability, compactibility and compressibility were investigated. The sample with IBU-NIC-Sol cocrystal formulation outperformed all the other formulations in terms of tabletability, compactibility and compressibility. Interestingly, this sample was even superior to the IBU-NIC cocrystal sample which verified the advantageous effect of the presence of an excipient. Moreover, dissolution test confirmed a noticeable increase in the dissolution of not only the cocrystal samples but even the physical mixtures of IBU and NIC compared with pure IBU.

Particle engineering of excipients: A mechanistic investigation into the compaction properties of lignin and [co]-spray dried lignin.

In this work, lignin was spray dried with sodium lauryl sulphate (SLS) in order to improve the compaction properties of lignin. Bulk level and physicochemical properties of spray dried formulations were measured and compared to as-received lignin and lactose which was used as a reference excipient. Single component tablets from individual powders were prepared and the mechanical properties of these powders were investigated by analysing force-displacement curves recorded during tableting, using a series of compaction equations. Moreover, the performance of these excipients in binary blends containing an active pharmaceutical ingredient (API) was investigated. A positive effect of SLS on the mechanical properties and bulk level properties of the spray dried formulations was observed. Spray dried formulations containing SLS showed superior flow properties to pure spray dried lignin while retaining similar particle size distributions. Spray dried formulations containing up to 10 w/w% SLS also showed superior compactibility in binary blends to as-received materials at porosity levels relevant for immediate release tablets. This study highlights the importance of understanding the compaction mechanics of single component powders as a means of predicting their behaviour in multi-component blends.

Spray drying of pharmaceuticals and biopharmaceuticals: Critical parameters and experimental process optimization approaches.

Spray drying is increasingly becoming recognized as an efficient drying and formulation technique for pharmaceutical and biopharmaceutical processing. It offers significant economic and processing advantages compared to lyophilisation/freeze-drying techniques even though the optimisation of process parameters is often a costly and time-consuming procedure. Spray Drying has primarily been used in formulating small molecule drugs with low solubility however it is increasingly being applied to the processing of large biomolecules and biopharmaceuticals. This review examines the basics of spray drying process, current technology and various components used in spray drying process. Moreover, it is focused on introducing critical formulation and processing factors in spray drying of small molecule drugs and large biomolecules, their similarities and differences. Finally, it provides an overview of the experimental optimisation strategies designed to achieve optimum spray drying results in the shortest possible timeframe while utilising minimum product.

Spray drying ternary amorphous solid dispersions of ibuprofen - An investigation into critical formulation and processing parameters.

A design of experiment (DoE) approach was used to investigate the critical formulation and processing parameters in spray drying ternary amorphous solid dispersions (ASDs) of ibuprofen. A range of 16 formulations of ibuprofen, HPMCP-HP55 and Kollidon VA 64 were spray dried. Statistical analysis revealed the interrelation of various spray drying process conditions and formulation factors, namely solution feed rate, inlet temperature, Active Pharmaceutical Ingredient (API)/excipients ratio and dichloromethane (DCM)/methanol (MeOH) ratio. Powder X-ray diffraction analysis (PXRD) showed that all the samples with the lowest API/excipient ratio (1:4) were amorphous, while others were crystalline. Moreover, differential scanning calorimetry (DSC) analysis was employed to investigate ASD formulation more in-depth. The glass transition temperatures (Tg) of all ASDs were in the range 70-79°C, while crystalline formulations displayed an endothermic peak of melting of crystalline ibuprofen in the range of 50-80°C. The high Tg of ASDs was an indication of highly stable ASD formulations as verified via PXRD at zero day and afterward at 1, 1.5, 3 and 6month intervals. The intermolecular interactions between ibuprofen molecule and excipients were studied by Fourier transform infrared spectroscopy (FTIR) and solid-state nuclear magnetic resonance (ssNMR) spectroscopy. FTIR and Carbon-13 ssNMR analysis indicated that hydrogen bond formation involving the carboxyl group in ibuprofen within the ASDs is likely. More importantly, the solubility of ibuprofen in ASD formulations is improved compared to pure ibuprofen. This was due to both the amorphous structure of ibuprofen and of the existence of amphiphilic excipient, Kollidon VA 64, in the formulation.