Advanced-Troubleshooting-For-Spray-Drying--Of-Pharmaceuticals

INTRODUCTION

Spray drying offers multiple opportunities for improving the formulation of both  poorly soluble pharmaceutical compounds and inhaled drug products. However,  while spray drying is a well-established manufacturing operation, it presents  certain challenges throughout the drug development process. This article examines  critical aspects of formulation development for spray-dried powders and the risk  mitigation strategies that may be applied to address a range of common issues  during production.

FUNDAMENTALS OF SPRAY DRYING

Spray drying is a process used to convert a solution containing dissolved solids into  a fine powder. It is proven to be particularly valuable for the creation of amorphous  solid dispersions (ASDs) of drug substances to enhance their solubility and oral  bioavailability, as well as in the development of improved formulations for inhaled  drug products.

Creating amorphous forms of active pharmaceutical ingredients (APIs) involves  spray drying solutions of organic solvents containing the drug and polymers. As solution is pumped into the spray drying chamber through a nozzle, finely  atomized droplets are created and rapidly dried in a stream of hot gas. The  resulting fine powder, often referred to as a spray-dried dispersion (SDD), is  collected in a cyclone.

An understanding of how the solution is atomized and how quickly it is dried  is crucial to controlling the spray drying process and the properties of the resulting powder.

CONSIDERATIONS IN EARLY PHASE DEVELOPMENT

Key goals in early phase drug development (preclinical to first-in-human studies)  include assessing drug safety with increasing doses, demonstrating initial signs  of efficacy in animal models, and ultimately proceeding into the clinic, often while  managing an often-limited supply of API.

For APIs with poor solubility, SDDs are often used to improve  drug solubility and oral bioavailability to reach sufficient and  consistent systemic exposure in order to collect high quality  in vivo data. At this stage, the goal of SDD development is to identify drug/polymer combinations that are capable of  delivering enhanced dissolution and robust physical stability,  ideally at high drug loads. An SDD development scheme can  be carried out using API sparing techniques that minimize  waste and ensure efficient use of limited API. When selecting  the drug loading, polymer, and solvent system, developers  must consider the effects of their choices on the ability to  produce the SDD-based drug product at increased scales.

Solvent Selection

Selecting the solvent system for use in spray drying is an  important early step in developing the SDD  protocol. Initial  screening involves examining multiple organic solvents with the  goal of achieving at least 50 mg/g of API in solution (around 5% drug load) and maintaining stability for three days. The  extended stability of the API in solution is important for late-  stage development and manufacturing as spray drying a single  batch at commercial scale could potentially take several days to  complete. If this proves impossible with using only one solvent,  the solubility and stability of the API can be tested in mixtures of two solvents at 20/80 and 80/20 ratios. After an appropriate  system is identified, initial spray drying can proceed.

Commonly used solvent types include alcohols (e.g., ethanol,  isopropanol), ketones (e.g., acetone), chlorinated solvents  (e.g., dichloromethane), and esters (e.g., ethyl acetate). Key  considerations influencing solvent choice include passing the  residual solvent specifications that must be met in the finished  product as well as solvent compatibility with the spray drying  equipment. Finally, the solvent boiling point will be integral to  developing the spray drying conditions to produce the SDD.

Polymer Selection

Another critical component of SDD development is polymer  selection, for which there are two key aspects to consider is the need for a polymer that will both stabilize the amorphous  state of the API; and one that maintains drug supersaturation  following dissolution.

An initial step in the polymer screening process is to use film  casting to examine combinations of the drug with a range  of polymers at different drug loadings to see which produce  amorphous films. Stress testing then determines which ones  remain amorphous upon storage.

The next step involves identifying a polymer that can maintain  drug supersaturation following dissolution by performing a liquid-liquid phase separation screen using fiber optic  micro-dissolution equipment. Here, polymer is pre-dissolved  in the dissolution medium at a known concentration. The  drug, dissolved in a water-miscible organic solvent at high  concentration, is then titrated into the dissolution medium. Monitoring response to ultraviolet light enables determination  of the point at which the drug comes out of solution, either  through crystallization or phase separation, permitting the  calculation of how much polymer is required to keep the drug  in solution.

The combination of these two experimental approaches  helps to determine which polymers at which drug loads  will be able to create physically stable SDDs capable of maintaining supersaturation of the drug in solution.  Some of the polymers commonly used to generate  SDDs include hydroxypropylmethyl cellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS),  polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate  (PVP-VA), and Eudragit® L100-55 (Evonik Industries AG).

The viscosity of the resultant solution for spray drying is  also important. High polymer concentrations often result  in high viscosity solutions, potentially creating issues  around atomization. In addition, the solution should ideally  have a total solids content of around 10% to ensure the  manufacturing process is efficient.

Evaluation of data from the above studies provides the initial  leads for laboratory-scale testing. Creation of SDDs using  small scale spray dryers, followed by their characterization,  allows for the identification and selection of solid dispersions  that are appropriate for scale-up for phase 1 clinical supply.

SCALE-UP FOR PHASE 1 CLINICAL SUPPLY

Initial development work on lab scale spray dryers is important  for optimizing the spray solution for solids content and  confirming the composition of the solid dispersion. When moving  to a larger spray dryer to manufacture SDD for phase 1 clinical  studies, it is important to explore different process parameters,  such as inlet and outlet temperatures, nozzle choice, atomization  pressure, and feed rate, and to then correlate the results with the  critical quality attributes (CQAs) of the SDD.

Making efficient use of the API, typically scarce at this stage, is  critical, and demands a clinical manufacturing process which  delivers high yield and minimal loss to fines. Additionally, when  transferring from lab to clinical scale, the secondary drying  technique becomes important since there may be a switch from  a lab-scale vacuum oven to a rotary dryer to facilitate faster drying. Once early-phase clinical supply is established, the SDD  can proceed forward for further product development.

LATE PHASE SCALE-UP AND TROUBLESHOOTING

When transitioning from early-phase to late-phase clinical  manufacturing, key goals include increasing production  capacity, optimizing CQAs and mitigating risk. Here, the use  of science and experience-driven scale-up methodologies  helps de-risk scale-up and makes troubleshooting easier  should problems occur during manufacturing. It is imperative  to start linking material attributes and process parameters to the desired product quality attributes and to understand the differences in throughput, key processing parameters and capital equipment size (FIGURE 1) as a program is scaled up.  Conducting risk assessments throughout the entire process  helps mitigate any challenges that may arise.

The scale-up process can be divided into easily solvable  thermodynamic elements (e.g., calculating outlet saturation,  selecting inlet/outlet processing temperatures, calculating  droplet residence time, and determining recycled gas  composition), and empirically determined elements (e.g. atomized droplet size, cyclone efficiency, SDD sticking in the  dryer, and powder flowability). It helps to think in terms of  the impact of starting material attributes and the process  parameters on the SDD product attributes.

Image showing Spray for Scale Comparison in Pharma companies                                                   Figure 1: Spray for Scale Comparison

 

For example, the API is most often required to be completely  amorphous in the finished SDD to achieve the desired solubility  enhancement. Polymer selection and API solubility in the solvent  blend are key material attributes that affect the physical state of  the API in the SDD. Critical process parameters that can have an  impact on the presence of crystalline API in the SDD are outlet  saturation and outlet temperature, which control the drying  kinetics of droplets. Another example of a product attribute that  needs to be controlled is particle size, as it can influence the  dissolution and flowability of the spray dried powder. Particle  size is impacted by polymer selection and excipient variability on  the material attributes side, and by process parameters such as  outlet saturation, outlet temperature, solids content and nozzle  selection. Excipient variability, often overlooked, is an important  consideration during late-stage development, especially when  there is a need to evaluate secondary suppliers of excipients. With variations in grade from different vendors, understanding  the impact of any changes in excipient properties on product  attributes is crucial.

IMPORTANCE OF RISK ASSESSMENTS

Risk assessments are valuable tools that help when prioritizing  resources and providing quick references for troubleshooting.  The most basic form of risk assessment is risk ranking, which  examines the severity of a risk and likelihood of occurrence. Determination of risk level then guides prioritization of time and the level of control required for risk mitigation.

For example, API degradation in solution exemplifies  a high-risk event, potentially resulting in an out-of- specification product, and as a result demands tight control. Alternatively, poor cyclone efficiency would present  a much lower risk if enough material can still be produced to meet program requirements.

Material processability challenges and equipment-driven  issues can also be addressed using risk assessments and  troubleshooting guides. For example, SDDs may have issues  with powder flowability, a product attribute of the spray-dried  intermediate that requires control and troubleshooting during  scale-up. Poor flowability generally arises from the low bulk  density and small particle size of materials. The issue can be identified through physical characterization of the SDD and clear  communication between the spray drying and solid oral dosage  development teams to understand its impact on the ability to  produce the final product. Overcoming poor flowability of an  SDD can be achieved by adjusting atomization to create larger  droplets, altering the drying conditions to produce more dense  powders, and optimizing the spray drying solution by increasing  solids content, if feasible.

It is important to understand that if problems are identified  and troubleshooting is required, there are always elements of  the formulation or process that can be changed to achieve the  desired product attributes and optimize process efficiency.

SPRAY DRYING LIPID-BASED FORMULATIONS

In drug delivery, lipids offer the benefits of low toxicity and  good biocompatibility, and spray drying is increasingly  being used for the provision of carrier-free delivery of dry powders for inhalation. Here, the use of readily inhalable lipid microparticles avoids many of the drug delivery inefficiencies  associated with conventional carrier particles. Lipids are  known to enrich the surface of the particle during spray  drying, enhancing aerosolization and improving dry powder  inhaler (DPI) performance. Spray drying also allows for tuning  of different attributes for more effective respiratory targeting.

Rational process design is helping overcome the challenges  of spray drying lipids, the most significant of which are their  low melting temperatures (Tm), multi-phase complexity, and polymorphism. This approach combines critical material attributes  (CMAs) with process parameters and process performance to  produce simple lipid-based formulations at high yields. It begins with selecting lipids with the highest possible melting point. A pre-  formulation step then examines any interaction between the lipid  and drug or lipid and solvent that might impact the melting point  or polymorphism of the formulation. The resulting information is  used to fix the boundary for the spray dryer outlet temperature.  The following proof-of-concept case study demonstrates the  general applicability of this approach.

Proof of Concept

The diagram in FIGURE 2 provides details of two different drug  delivery applications using lipid-based formulations and the  specifications required. Taking the systemic delivery formulation  as the exemplar, the first step is to select relatively high melting  point lipids. In this case, polyglycerol esters of behenic acid  showed the best performance. Pre-formulation solvent casting  using lipids and varying amounts of ibuprofen helped predict  the solid-state outcome from spray drying. When testing the lipid PG3C22p, the results showed that even though the  selected lipid had a melting point of around 74°C, interactions

between the lipid and ibuprofen caused the melting point of a  mixture of 30% ibuprofen and 70% lipid to be closer to 60°C. An  efficient spray drying process could be developed by selecting  an outlet temperature sufficiently below 60°C. Once the outlet  temperature is established, it is possible to define process  parameters to achieve target particle attributes.

Experimentation using a variety of different lipids revealed that  a difference of at least 20°C between the melting point of the  mixture and outlet temperature provided the highest yields and  the least agglomeration in the system. However, this alone was  insufficient to achieve good yields for all lipid types, so it was  necessary to look at the particle trajectory inside the drying chamber. Issues such as entrapment of particles, recrystallization,  wall deposition, process loss and agglomeration at the outlet all affect yield. Screening with differential scanning calorimetry (DSC) at the pre-formulation stage helped determine Tm and  crystallization behavior, enabling for selection of the correct inlet  and outlet temperatures.

CONCLUSION

In reviewing some of the challenges involved in spray drying  for pharmaceutical applications, a science and experience-  based approach to development and scale-up is needed to  ensure efficient use of available resources, especially with the  growing use of ASDs for solubility enhancement. Taking action  to identify critical process steps and mitigate the risks at each  stage is crucial for success.

In the quest for carrier-free inhaled drug products, the use of  spray dried lipid formulations is being researched as a potential  solution. As  with SDDs, rational process design can help improve  yields and increase the viability of these products.

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product development, launch, and full Selecting the solvent system for use in spray drying is an  important early step in developing the SDD  protocol. Initial  screening involves examining multiple organic solvents with the  goal of achieving at least 50 mg/g of API in solution (around 5% drug load) and maintaining stability for three days. The  extended stability of the API in solution is important for late-  stage development and manufacturing as spray drying a single  batch at commercial scale could potentially take several days to  complete. If this proves impossible with using only one solvent,  the solubility and stability of the API can be tested in mixtures of two solvents at 20/80 and 80/20 ratios. After an appropriate  system is identified, initial spray drying can proceed.

Commonly used solvent types include alcohols (e.g., ethanol,  isopropanol), ketones (e.g., acetone), chlorinated solvents  (e.g., dichloromethane), and esters (e.g., ethyl acetate). Key  considerations influencing solvent choice include passing the  residual solvent specifications that must be met in the finished  product as well as solvent compatibility with the spray drying  equipment. Finally, the solvent boiling point will be integral to  developing the spray drying conditions to produce the SDD.

 

author avatar
Sridhar Gumudavelli
Sridhar Gumudavelli serves as the Vice President of Formulation R&D at Renejix Pharma Solutions, where he brings a wealth of knowledge and experience to the table. His leadership is instrumental in navigating the complex process of drug formulation, leveraging a variety of technologies to enhance drug absorption, bioavailability, and patient compliance.Sridhar’s expertise is not just limited to his hands-on experience; he is also an innovator with several patents filed under his name. These patents reflect his contributions to advancing drug delivery systems, showcasing his ability to tackle some of the most challenging problems in pharmaceutical sciences for the past 30+ years.

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