Ziaee_2019_Spray.pdf (5.63 MB)
Spray drying of pharmaceuticals and biopharmaceuticals: experimental optimization of process and formulation
thesisposted on 2022-09-21, 10:58 authored by Ahmad Ziaee
Oral consumption is the most commonly used method of small molecule drug delivery due to its simple administration, flexible formulation design, cost-effectiveness and established production technology. The typical pathway for an orally ingested drug involves dissolution in the gastrointestinal fluid, followed by permeation across the gut membrane and systemic circulation until it reaches the point of action. The rate of dissolution is therefore of critical importance to ensure high drug adsorption and maximum efficacy. The Biopharmaceutical Classification System (BCS) classified active pharmaceutical ingredients (APIs) into 4 categories based on their solubility and permeability among which BCS class II APIs are defined as being poorly soluble but highly permeable. The share of BCS class II APIs of newly developed drugs has increased from 30% to 60% in recent years. Therefore, it is critical for the industry to incorporate effective formulation approaches for improving solubility and dissolution rates of these APIs. In this regard, a number of approaches have been investigated. Amorphous solid dispersion (ASD) is a successful approach for transforming and stabilizing crystalline drugs to amorphous form with higher solubility/dissolution rates. Spray drying (SD) is a solvent-based drying method that has been used for formulating ASDs with improved solubility and stability. Biopharmaceuticals are pharmaceuticals that are inherently biological in nature and manufactured using biotechnology. This broad definition includes any type of blood product, vaccines, antibodies, proteins and nucleic acids. Protein-based pharmaceuticals are among the fastest growing categories of therapeutic agents. Therefore, the development of stable protein based formulations with controlled physicochemical properties is of high interest. Reversible and irreversible aggregation in liquid protein formulations specifically at high concentrations is a challenging problem for biopharmaceutical producers. Spray drying is (SD) is a solvent-based technique in which solutions are atomized and dried using heat in a drying chamber. It is known for its high throughput and compatibility with continuous manufacturing. SD has previously been demonstrated as an effective technique for the preparation of ASDs and it has been used as an alternative method to freeze-drying for drying and stabilizing high concentration formulations of biopharmaceuticals. To date however, the development of spray drying processes for large biomolecules has proved challenging primarily due to protein/enzymatic inactivation caused by high drying temperatures and the shear stress induced by atomization. Overcoming this issue will require a comprehensive understanding of the effect of formulation and process parameters on spray dried biological formulations. Chapter 1 reviews the fundamental principles of SD by explaining every individual step of the process from atomization to the drying chamber set up. It comprehensively covers the applications of SD in preparing ASDs and formulating stable biopharmaceuticals. The effect of process and formulation parameters on SD of biopharmaceuticals such as vaccines and proteins for pulmonary delivery applications are discussed. This follows an attempt to elucidate the systematic use of the Design of Experiment (DoE) approach for optimizing the SD process for different applications to conclude this chapter. Chapter 2 highlights the use of the DoE approach for formulating ternary ASD compositions of Ibuprofen (IBU) as a model BCS class II API. Based on the DoE approach a range of 16 formulations of IBU, HPMCP-HP55 and Kollidon VA 64 were spray dried. Statistical analysis was employed to decipher the interrelation of various SD process and formulation factors, namely solution feed rate, inlet temperature, API to excipients ratio and dichloromethane (DCM) /methanol (MeOH) ratio. The significance of composition (IBU:excipient) was shown as the determining factor in preparing stable ASD formulations. The effect of intermolecular interactions was investigated by Fourier-Transform Infrared spectroscopy (FTIR) and Carbon-13 Solid-State Nuclear Magnetic Resonance spectroscopy (ssNMR) analyses indicating that hydrogen bond formation between the carboxyl groups of IBU within the ASDs is highly likely. Studies show that the solubility of IBU in ASD formulations is improved relative to pure IBU. This was attributed to both the amorphous structure of IBU and of the existence of amphiphilic excipient, Kollidon VA64, in the formulation. This study indicates that ASD is an effective strategy for improving the dissolution rate of IBU as a BCS class II API. Chapter 3 investigates the influence of three different solvent-based techniques on the physicochemical properties and quality of ASDs of IBU. Solvent-based techniques of electrospinning (ES), spray-drying (SD) and rotary evaporation (RE), were used for formulating ASDs of IBU as a model BCS class II API with two cellulosic excipients, HPMCAS and HPMCP HP55 in an attempt to determine the effect of processing technique on the critical quality attributes (CQAs) of ASDs. Principal component analysis (PCA) of Raman spectra of crystalline and amorphous IBU was used for qualitative analysis of the homogeneity of ASDs as a determining factor for the stability of ASDs during long-term storage. Results show that while ASD formation is solely dependent on API:excipient ratio, the ASD homogeneity is totally dependent on the processing technique. Samples produced by ES gave the least homogenous ASD compared with RE and SD samples potentially influencing long-term storage stability. Moreover, ES samples had the highest API release rate which was further confirmed to be due to the nanofibrous morphology and higher specific surface area of these samples. The presence of crystalline IBU in samples and the ASD forming strengths of each of the polymers was assessed by Differential Scanning Calorimetry (DSC). The higher melting point depression, higher glass transition temperature (Tg), and increased abundance of functional groups suitable for hydrogen bonding of HPMCAS proved it to be a significantly better ASD former relative to HPMCP-HP55. This chapter concludes by outlining the significance of the three solvent-based processing techniques (ES, SD and RE) on the physicochemical properties of ASDs such as dissolution rate, specific surface area and homogeneity, factors that could ultimately affect their stability and downstream processing capacity. Chapter 4 develops a rational approach towards the spray drying of biopharmaceuticals using lysozyme as a model biomolecule. A two-step approach is suggested towards a comprehensive understanding of the behaviour of large biomolecules during the spray drying process with a view to developing tailored spray drying protocols for biological molecules. A full factorial Design of Experiments (DoE) was employed to define the most critical process and formulation parameters. With respect to parameters such as feeding rate, outlet temperature (Tout) and feed solid concentration, Tout was determined to be the most statistically significant factor affecting the enzymatic activity of lysozyme based on screening analysis of the DoE. The second step of the study involved performing forced deactivation studies to identify critical points of potential enzymatic deactivation during the drying process. This was performed by investigating the inactivation of lysozyme both in solution and solid-state at wet-bulb (Twb) and outlet temperatures respectively. Results show that there is no substantial inactivation of lysozyme in solution at Twb (35-45 °C). However, lysozyme in solid form experienced a significant degree of inactivation when heated to temperatures similar to Tout (70-90 °C). This inactivation was fitted by an Arrhenius equation, where the inactivation energy and Arrhenius constant were estimated. The approaches and models presented herein provide a roadmap for improved understanding of the critical process and formulation parameters required for the successful spray drying of large biomolecules. Chapter 5 summarises the additional contributions the author made during his Ph.D. period. It consists of a brief introduction to the results of three different projects on which the author is listed as a co-author: 1. Particle engineering of lignin via spray drying as a potential excipient for the pharmaceutical industry. 2. Co-crystal polymorphic control by nanodroplet and electrical confinement. 3. A study on the effect of polymeric excipient on the downstream processing of hot-melt extruded cocrystals of ibuprofen. Chapter 6 provides a conclusive overview of the whole thesis. Chapter 7 discusses potential future directions in the field of spray drying of pharmaceuticals and biopharmaceuticals. If applied correctly spray drying as one of the leading continuous drying and formulating techniques in small molecule sector possess immense potential to become a major player in processing large molecule APIs as well. This thesis follows two main objectives: Firstly, developing novel ternary amorphous solid dispersions via spray drying for improving the dissolution and physicochemical properties of BCS class II APIs. In an attempt to meet this goal, the design of experiment (DoE) approach as part of the quality by design (QbD) strategy in pharmaceutical and biopharmaceutical industry was used for simultaneous analysis of interrelations of process and formulation techniques. Chapters three and four are focused on spray drying novel ternary amorphous solid dispersion of ibuprofen as a small molecule API with low aqueous solubility.