DRUG DEVELOPMENT - Improving Bioavailability & Solubility in OSDs

INTRODUCTION

The majority of drug candidates emerging from contempo­rary drug discovery pipelines exhibit too low aqueous solubility to allow for adequate absorption after oral intake. Over 90% of drug substances have bioavailability limitations, of which 70% are related to solubility challenges.

Formulators have multiple technologies available to enhance solubility or dissolution rate for drug products including oral solid dosage (OSD) forms, but there is no such thing as a one-size-fits-all solution. Selection of a formulation approach must be done in light of the physicochemical profile of the drug candidate, its permeability and its dose. In the early stages of drug develop­ment, selection is biased towards technologies that enable high drugloads, have low manufacturing complexity and high admin­istration flexibility.

In this article, Hibreniguss Terefe (PhD), Director of Product Development, Ardena, explores the options available to improve bioavailability and solubility and provides guidance to support decision-making when designing oral formulations for poorly sol­uble drug candidates in early development.

FORMULATION APPROACHES TO ADDRESS SOLUBILITY CHALLENGES

Particle size reduction for crystalline active pharmaceutical ingredients (APIs) can improve rate of dissolution by increasing the surface area available to come into contact with the solvent. This requires specialized technologies such as nanomilling, care­ful formulation development and multiple process steps to reduce the particles to the precise and uniform size needed for controlled dissolution.

Alternatively, amorphous solid dispersions (ASDs) can be used. An ASD is a solid material that lacks the organized atomic structure typically found in crystalline solids. ASDs exhibit a single glass transition temperature. These materials possess higher en­ergy states, leading to faster dissolution rates and increased sol­ubility.

The process of creating an ASD involves converting a crys­talline API into an amorphous form and then embedding it within a polymer carrier. Spray drying, a solvent based method or hot melt extrusion, a fusion based method could be used to make amorphous solid dispersions. Lipid formulation approaches, such as lipid-based drug delivery systems (LBDDS) is another ap­proached used to improve bioavailability.

Hot melt extrusion (HME) is a particularly effective technology to manufacture ASDs. HME has many benefits, including:

• Fewer processing steps: Compared to other ASD manufac­turing methods, which can shorten production time and cost of goods (COGS).
• No solvents: This can reduce patient safety concerns and de­velopment costs.
• Continuous process: minimizes scaleup efforts by increasing batch size as a scale of time instead of equipment size.
• Versatile: HME can be used to make many types of OSD forms, including tablets, minitablets, pellets, capsules, and sa­chets.

The choice of method – whether HME is chosen, or another method entirely – depends on specific formulation considerations.

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PRE-FORMULATION DEVELOPMENT: PHYSICOCHEMICAL EVALUATION At the pre-formulation development stage, physicochemical evaluation plays a crucial role in understanding the materials involved and ensuring appropriateness for HME formulation in terms of thermal sta­bility, processibility as well as physical and chemical stability up on storage. The ob­jective of this evaluation is to gather com­prehensive information about the drug substance, polymer, and other additives to lay the foundation for successful product development.

When considering the potential suit­ability of a drug substance for HME, a number of factors should be explored.

For the drug substance, various prop­erties are assessed, including the melting temperature (Tm), glass transition temper­ature (Tg), thermal degradation tempera­ture (Tdeg), molecular weight (MW), pH solubility profile, solvent solubility, pKa, logP, logC, as well as the presence of hy­drogen bonding acceptor/donor groups. Additionally, the degradation pathway and chemical stability of the drug substance are investigated.

Similarly, the polymer used in the for­mulation undergoes evaluation, consider­ing its MW, Tm, Tg, Tdeg, and the presence of hydrogen bonding donor/ac­ceptor groups. Viscosity, an important property for processing, is also considered.

Other additives such as plasticizers, surfactants, and process aids are assessed for their properties and compatibility with the formulation.

To conduct these evaluations, various tools are utilized, including differential scanning calorimetry (DSC), thermogravi­metric analysis (TGA), hot stage mi­croscopy (HSM), and x-ray powder diffrac­tion (XRPD). These tools provide valuable insights into the thermal behavior, stability, and crystallinity of the materials.

Approximately 100mg of the drug substance is typically required for these characterization tests. The physicochemi­cal properties of the drug substance are thoroughly reviewed by examining techni­cal data, development reports, and rele­vant literature to gather available information. In cases where information gaps exist, API characterization tests are conducted to fill in the missing details.

Understanding the physicochemical properties of the drug substance and hav­ing knowledge of the potential excipient properties are crucial for successful formu­lation development. This pre-formulation evaluation sets the stage for further formu­lation optimization and ensures the quality and effectiveness of the final product.

PRE-FORMULATION DEVELOPMENT: THERMODYNAMIC ASSESSMENT

At the pre-formulation development stage for HME ASDs, a thermodynamic as­sessment is conducted to select the appro­priate carrier polymer and evaluate the drug load (DL) for the formulation. Addi­tionally, the interaction between the drug substance and the polymer is thoroughly evaluated.

Miscibility studies are conducted be­tween the drug substance and four to five polymers, considering two to four different drug loadings. The assessment includes the evaluation of melting point depression, the Tg of the ASD, polymorphism, and the propensity of the amorphous drug sub­stance to recrystallize within the polymeric matrix.

A phase diagram is constructed to il­lustrate the impact of drug loading on crit­ical factors such as processing temperature, degradation temperature limit, solubility of the drug substance in the molten polymer, as well as the recrystal­lization curve. This diagram provides valu­able insights into the formulation process and helps optimize the drug-polymer sys­tem.

To conduct these assessments, various tools are utilized, including DSC, thermal rheometer, HSM, XRPD, and the construc­tion of a phase diagram.

Approximately 1g of the drug substance is typically required for these as­sessments. The thermodynamic assess­ment focuses on understanding the interaction between the drug substance and the polymer, ensuring compatibility and optimizing the formulation for the HME process.

FORMULATION DEVELOPMENT: API SPARING HME FEASIBILITY

At the formulation development stage, the primary objective is to assess the feasibility of HME and identify potential formulations that ensure compatibility, per­formance, and stability upon storage.

The process begins with a screening phase, where two to three polymers are carefully evaluated along with three differ­ent DL values. Consideration is given to the impact of processing temperature range and time, and additives such as plasticizers and surfactants are incorpo­rated as needed.

Comprehensive characterization of the formulations must then take place. This involves assessing various aspects includ­ing amorphicity, related substances, super saturated kinetic dissolution (SSKD), phys­ical stability, chemical stability, and bioavailability, using a range of tech­niques.

A notable approach is vacuum com­pression moulding (VCM) combined with prior cryomilling, which optimizes the suc­cess probability while minimizing API usage. With this method, it becomes pos­sible to evaluate up to 12 experimental conditions using less than 100mg of API, resulting in significant API savings com­pared to using an 11mm extruder where at least 20g of API would be required to perform the same number of experiments.

Additionally, if force degradation data is not available for the API, the VCM tech­nique can be used to quickly assess accel­erated API degradation and study excipient compatibility, which would other­wise take 4 weeks using conventional sta­bility studies. Other tools utilized in the formulation development process include: polarized light microscopy (PLM); DSC; XRPD; dissolution testing; high-perfor­mance liquid chromatography (HPLC), and animal pharmacokinetic (PK) studies.

In terms of batch size, the API sparing feasibility studies typically involve working with 100-200mg of the formulation, while the API requirement can vary depending on the drug loading. As a result, approxi­mately 5g of API would be needed, which could include a series of experimental batches and some material for preliminary animal PK study. Alternatively, utilizing a 11mm extruder, one to two batches only at a 20% DL would require 10-15g of API.

The formulation development stage focuses on sparing the API while thor­oughly assessing the feasibility of HME and optimizing the formulation for com­patibility, performance, and stability during storage. This approach allows for efficient pre-clinical supply with minimal API usage and aids in determining whether HME is the ideal technology for the specific mole­cule under development.

FORMULATION DEVELOPMENT: PROTOTYPING

A viable formulation must be estab­lished for further optimization and evalu­ation through prototyping.

Prototyping involves assessing the im­pact of critical material attributes (CMA), both qualitatively and quantitatively, on critical quality attributes (CQA) such as amorphosity, related substances, physical stability, and chemical stability.

The extrusion process evaluation aims to assess the impact of critical process pa­rameters (CPP) on CQA. This includes evaluating factors such as screw design, processing temperature profile, feed rate, and screw speed. An 11mm extruder is typically used along with various tools in­cluding DSC, XRPD, dissolution testing, and HPLC.

The batch size for prototyping typically ranges from 20-50g. The API requirement for this stage is approximately 50 – 100 g depending on the drug loading.

By carefully assessing the impact of formulation components and process pa­rameters on critical attributes, the goal is to develop a robust formulation that meets the desired quality and performance criteria.

PROCESS DEVELOPMENT: ESTABLISHING A ROBUST & SCALABLE PROCESS FOR CONSISTENT PRODUCT QUALITY

At the process development stage, the primary objective is to establish a robust and scalable HME process that ensures consistent product quality. This involves conducting an extrusion process design of experiments (DOE) to determine the de­sign space, identify failure points, and de­fine scale-up factors. Additionally, optimization of upstream and downstream processes, as well as manufacturing of clinical trial material (CTM) and conduct­ing stability studies per International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), are key objectives.

The DOE factors considered in the process development include independent variables such as screw design, process temperature profile, feed rate, and screw speed. These variables are carefully eval­uated to understand their impact on the extrusion process and product quality.

Dependent variables, including melt temperature, percent load (%torque), res­idence time distribution, and specific me­chanical energy, are measured to assess the performance and characteristics of the extruded product.

To conduct these evaluations, an 18mm extruder is typically used along with the same analytical tools from previous stages. The batch size for process devel­opment typically ranges from 5-25kg, de­pending on the scale of production. The API requirement for this stage is approxi­mately 0.5-2kg depending on the drug loading. For early phase clinical studies with smaller clinical material requirement smaller batch sizes could be considered.

The process development stage fo­cuses on establishing a robust and scala­ble process that can consistently produce high-quality products. By conducting DOE experiments and analyzing various process variables, the goal is to optimize the extrusion process, ensure product quality, and prepare for scale-up manu­facturing. Additionally, stability studies fol­lowing ICH guidelines are conducted to assess the long-term stability and shelf-life of the manufactured product.

SCALE-UP AND PROCESS OPTIMIZATION: FINE-TUNING PROCESS PARAMETERS, OPTIMIZING EQUIPMENT CONFIGURATIONS & STREAMLINING WORKFLOW

At the scale-up and process optimiza­tion stage, the focus is on fine-tuning the process parameters, optimizing equipment configurations, and streamlining the work­flow to ensure successful commercial-scale manufacturing.

The objective is to scale up the HME manufacturing process and optimize it for commercial production. This includes specifying manufacturing process param­eter targets and ranges, as well as defin­ing process control strategies to ensure consistent product quality.

The DOE factors considered in this stage include independent variables such as screw design, process temperature pro­file, feed rate, and screw speed. These variables are carefully adjusted and opti­mized to achieve the desired product char­acteristics and performance.

Dependent variables, including melt temperature, % torque, residence time dis­tribution, and specific mechanical energy, are monitored and controlled to ensure the process operates within the desired pa­rameters and produces consistent results.

To conduct these evaluations, a 27mm extruder is typically used along with the previously mentioned analytical tools. These provide valuable insights into the physical and chemical properties of the product and help optimize the process.

The batch size for scale-up and process optimization typically ranges from 50-100kg, depending on the desired pro­duction scale. The API requirement for this stage is approximately 10-20kg depend­ing on the drug loading.

The scale-up and process optimiza­tion stage focuses on fine-tuning the man­ufacturing process, optimizing equipment configurations, and streamlining the work­flow for efficient commercial-scale produc­tion. By carefully adjusting process parameters, controlling variables, and uti­lizing advanced analytical tools, the goal is to achieve consistent product quality and ensure a smooth transition from lab-scale to commercial-scale manufacturing.

STRATEGIES FOR SUCCESS

Keeping all of this guidance in mind, and by harnessing HME, organizations can enhance the drug development process, reduce costs, and expedite the journey from early development to clinical studies. These strategies contribute to over­all success and enable timely delivery of safe and effective formulations to patients in need.

Dr. Hibreniguss Terefe is the Director of Product Development at Ardena US in Somerset, New Jersey, a leading contract development and manufacturing organization (CDMO). He is responsible for the development of preclinical and clinical solid oral dosage forms, overseeing their transition to commercial manufacturing through both conventional and specialized pharmaceutical manufacturing processes. Prior to this role, Dr. Terefe served as Director of Research and Development at Catalent Pharma Solutions in Somerset from April 2021 to January 2024, where he led the product development department. Following Ardena’s acquisition of the Somerset site in February 2024, he transitioned to his current position. Dr. Terefe brings over 27 years of experience in pharmaceutical research, development, and manufacturing. He previously spent 14 years as Vice President of Research and Development at ExxPharma Therapeutics and nine years as Head of the Department of Pharmacy at the University of Asmara, Eritrea. A recognized expert in pharmaceutical research and development, Dr. Terefe has extensive expertise in drug product development, commercial manufacturing, and Chemistry, Manufacturing, and Controls (CMC). His core competencies include solubility enhancement, modified-release solid oral dosage forms, drug delivery system development, and twin-screw extrusion processes. With more than 18 years of experience in Hot Melt Extrusion, he has led product development efforts for new chemical entities (NCEs) from preclinical stages through Phase III clinical development, utilizing advanced drug delivery technologies and specialized pharmaceutical manufacturing techniques. Dr. Terefe holds a PhD in Pharmaceutical Chemistry and a Pharmacy degree from Westfälische Wilhelms-Universität Münster, Germany. He was also a Fulbright Visiting Scholar at the University of California, Berkeley.