Nozzle Selection During Process Development of a Pharmaceutical Spray Dried Solid Dispersion

Spray drying is a common unit operation across many industries due to the ability to control bulk powder properties and isolate dry product from a liquid feed in a single operation. For the pharmaceutical industry, spray drying offers the control of physical properties of crystalline or amorphous active pharmaceutical ingredients (APIs), as a neat or formulated drug product that can lead to improved bioavailability of the drug candidate. Drug candidate molecules are often formulated as a solid dispersion, incorporating both API and a polymer excipient for enhanced dissolution performance and improved physical stability. Bulk density and particle size of the spray dried dispersion can impact downstream manufacturability as well as performance of the dosage form. Robust ranges should be explored during development while minimizing the use of high-cost and limited supply API. For Compound A, formulated as a spray dried amorphous solid dispersion for oral delivery, atomization was decoupled from the drying process and a Phase Doppler Particle Analyzer was used to determine the appropriate nozzle for several different particle size targets. The selected nozzles were then used within a pilot scale spray dryer to produce product with the desired particle size and density combinations for downstream manufacturability testing. Corresponding author: [email protected] ILASS Americas 28th Annual Conference on Liquid Atomization and Spray Systems, Dearborn, MI, May 2016 Introduction As the complexity of new pharmaceutically relevant compounds have increased, so has the challenge of efficiently and effectively delivering the active pharmaceutical ingredient (API). Estimates range from 40% and upwards as to the percentage of APIs currently in development that have limited aqueous solubility [1]. To address these challenges, the pharmaceutical industry has applied a variety of techniques to improve API properties for delivery, namely amorphous solids dispersions [2,3]. By preparing the active ingredient as an amorphous material, a higher energy state is attained, offering higher bioavailability. In order to promote physical stability of the higher energy amorphous form in the solid state, as well as inhibit crystallization during delivery of the active ingredient, the API is often stabilized within a carrier excipient (or inactive ingredient); typically a high glass transition polymer that is coprocessed with the API to form the intimately mixed solid dispersion. Spray drying is one of the most common techniques to produce an amorphous solid dispersion. Spray drying is used to 1) convert the API to the amorphous form by rapid solvent evaporation and 2) engineer the powder properties for optimal drug performance and successful downstream operation. Powder physical properties of interest are often density and particle size and may be identified as critical quality attributes of the spray dried product, reported and monitored with regulatory agencies, depending on the severity of impact to the patient and the ability to sufficiently control the process. Product density is controlled through the formulation of the solid dispersion (e.g., choice of polymer) as well as the selection of drying conditions within the spray dryer. Particle size is dictated by the size of the atomized droplet within the spray dryer. The selection of atomizer type is dependent upon the fluid properties. Based on the inclusion of a polymeric excipient in the amorphous solid dispersion feed solution a viscous feed solution is typical. Rationale for selection of atomizer type is well discussed elsewhere [4], leading to single fluid pressure nozzles as the atomizer of choice for most spray dried amorphous solid dispersions. The atomized droplet size is based upon the fluid properties of the feed solution and the atomization nozzle selected to produce the droplets. With each new investigational drug candidate, the properties of the molecule dictate not only the formulation of the solid dispersion, but also the selection of the feed solution solvent and operating conditions (e.g. temperature, pressure, solids concentration). Selection of the appropriate spray nozzle must account for an understanding of the fluid properties and droplet size targets, but also the thermodynamics of the spray drying operation. The nozzle operating pressure affects both the droplet size and the mass flow rate of the feed into the dryer for a single fluid pressure nozzle. Changes in atomization pressure impact droplet size, as well as the flow rate and hence the conditions within the drying chamber of the spray dryer. In order to decouple these processes, multiple nozzles are identified to 1) produce different product particle sizes at the same flow rate or 2) produce the same particle size across widely different flow rates, or 3) combinations thereof. Selection of a suitable single fluid atomizer for pilot scale spray drying operations will be discussed for Compound A, a poor soluble API current formulated as an amorphous solid dispersion prepared by spray drying. Objectives The objective of nozzle selection for Compound A was to sufficiently understand the atomization of the feed solution to meet the particle size target of 30 μm. This was accomplished in several stages: 1. Preliminary Nozzle Identification: determine likely nozzles to be used for the process, given nozzle characteristics and fluid properties 2. Water Flow Testing: quickly establish an acceptable stock of nozzles for further testing 3. Solution Characterization: to determine a suitable placebo solution 4. Pressure vs. Flow and Planar Spray Characteristics: Characterize a range of nozzles using solvent and placebo based solutions 5. Nozzle Recommendations: Select a nozzle(s) for pilot-scale studies Materials and Methods Preliminary Nozzle Identification In order to match the target particle size of the Compound A spray dried product, an understanding of the spray drying process parameters is important. The feed rate of the solution, not only contributes to the nozzle selection, but impacts dryer thermodynamics and operational efficiency. For pilot scale trials of Compound A, a maximum feed pressure of 1000 PSI and maximum feed solution flow ratesof 18 kg/hr were known based on pilot dryer equipment capability and capacity. The target powder particle size was based upon prior materials that had been used in clinical studies and the desire to match previous properties with a Dv,50 = 30 μm. While no specifications exists for the full particle size distribution, downstream processing is aided by a narrow, monomodal particle size distribution. One approach proposed previously is to apply a mass balance around the droplet-to-powder formation process, relating the true density of the product with the solids concentration of the liquid [5]. In the case of polymer droplet drying, the polymer forms a skin at the surface of the droplet, which results in product particle sizes smaller than, equal to, or larger than the solution