Understanding the impact of spray drying temperature on the dissolution behavior of a HPMC-AS spray dried formulation

Abstract

Spray dried dispersion (SDD) is increasingly used in solid dose formulations for poorly soluble active pharmaceutical ingredients (APIs). Dissolution was studied on a HPMC-AS based SDD and one important SDD manufacturing parameter, the spray drying outlet temperature (T_out), was found to significantly affect the dissolution rate of the tablet formulation containing the SDD. The dissolution rate of tablets containing SDD made at higher T_out was slower than those containing SDD made at lower T_out. When SDD powder dissolution was tested using a dissolution apparatus equipped with an intrinsic dissolution device, a similar trend of dissolution rate was observed. SEM imaging and other physical characterizations showed that the morphology of the SDD material contained a mixture of hollow sphere particles and collapsed, wrinkled raisin-like particles. Higher T_out produced a higher ratio of hollow sphere particles than lower T_out. It was found that although SDD T_out and particle morphology did impact the drug product properties such as tablet hardness, the dissolution rate difference was mainly attributed to the SDD particle dissolution instead of tablet disintegration for the model SDD formulation studied. To further understand the SDD particle dissolution rate differences at different SDD T_out, the raisin-like particles and the hollow sphere particles from the same batch of SDD were physically separated by density for dissolution study. The separated hollow sphere SDD particles showed slower dissolution compared to the raisin-like SDD particles in both SDD powder form and drug product tablet form. Additional physical characterization and surface analysis were conducted on the SDD materials to understand the mechanism of the dissolution rate difference. Surface composition analysis by x-ray photoelectron spectroscopy (XPS) suggested that a higher concentration of the drug substance was present at the surface of the hollow sphere SDD particles than raisin-like particles. It is possible that the higher concentration of the poor soluble API on the surface of hollow sphere SDD particles resulted in more hydrophobic surface which led to slower dissolution rate.

Introduction

Poorly water-soluble drugs are now accounting for ∼70% of new chemical entities.1, 2, 3 Spray dried dispersions have been demonstrated to significantly enhance the API solubility and therefore are increasingly used in solid dose formulations to boost drug bioavailability.4,5 Compared to other types of amorphous solid dispersion (ASD) techniques such as hot melt extrusion (HME), spray dried formulations requires a lower temperature during processing and it is especially suitable for less thermal stable and lower melting temperature drugs.2 Spray dried dispersions (SDDs) with different types of polymer and drug-polymer ratio have been studied for solubility and bioavailability enhancement in the drug product formulation development, especially in the early phase clinical formulation development.3,6,7

Drug dissolution rate is usually considered one of the critical quality attributes (CQAs) of the final drug formulation/product. Several studies have been reported to investigate the impact of SDD compositions and properties on SDD material and SDD formulation dissolution rate.8, 9, 10 H. Al-Obaidi and coworkers studied the effect of the spray drying solvent on dissolution rate.11 S. Kumar and coworkers studied the dissolution rate dependence on the spray drying particle size.12 The impact of drug ratio and drug molecular interactions in the SDD on dissolution have also been studied.13,14

Most of the dissolution studies on the SDD materials found in the literature have been focusing on early pharmaceutical and formulation development to enhance dissolution performance and bioavailability. It is correct that in the early stage of the formulation development, solubility and dissolution rate enhancement is the focus. When pharmaceutical development moves to the later phases, more focus will be put on fine tuning the dissolution performance and developing process controls to achieve desired and consistent dissolution rates. At this stage it is important to understand how the SDD manufacturing parameters impact the final drug product dissolution performance and the robustness of drug product dissolution. Development of the control strategy on SDD formulation becomes crucial to the success of a product. It was found that relatively fewer considerations have been given from the current publications to address the impact from SDD manufacturing parameters in the late phase pharmaceutical development. For drug products that contain SDD in the formulation, the SDD material can have a significant impact on the dissolution performance of the whole formulation. For this reason, a good overall drug product control strategy needs a sound SDD control strategy. Deeper understanding of the relationship between SDD manufacturing parameters and the finished product dissolution is important for knowing what parameters to control in the SDD manufacturing to ensure the drug product will meet the bioavailability requirements with consistent performance. It is often challenging to establish the link between the SDD properties to the final product dissolution behaviors since, normally, SDD will need to go through many steps of the downstream processing before the final drug product. The downstream processing may modify the SDD material properties and make the dissolution performance hard to predict. On the other side, an understanding of the impact from the SDD manufacturing parameters on the drug product dissolution performance can also be useful when determining the appropriate dissolution method and specification for the finished drug product.

SDD manufacturing conditions affect the drug product dissolution by altering the SDD material properties such as density and particle size. Several studies have been published to investigate the impact of manufacturing conditions to SDD particle properties.15, 16, 17 SDD properties can be affected by many spray drying conditions such as the spray drying temperature, solid loads, spray-dry solution feed viscosity, nozzle type and size, feed flow rate and atomization gas flow rate. One unique property of the SDD particles compared to other drug formulation components is the potential hollow structure generated by the spray drying process. Depending on the ratio between droplet evaporation rate and diffusional motion of the solutes, the SDD particle walls can deflate or inflate based on the partial pressure of the solvent trapped in the particle, which will result in either dense and solid particles or hollow and light particles.15 At certain conditions, the hollow spheres can be collapsed or fractured as well.16 The SDD particle morphology, including particle size, density, and surface area, can affect the downstream drug product formulation properties and drug product dissolution performance directly or indirectly.

The Spray Drying temperature is one process parameter among many other parameters that can affect the SDD particle morphology. The Spray Drying temperature has been shown to be very important to the SDD particle morphology in the SDD studies.15,16 The Spray Drying temperature is normally controlled by a set of Spray Drying parameters such as the Spray Drying inlet temperature, the gas flow rate and the liquid flow rate. The outlet temperature, Tout, has been used to represent the actual Spray Drying temperature. The SDD Tout was first identified in our SDD process development Design of Experiments (DOEs) to be one of the few process parameters that had significant impact on the drug product tablet dissolution rate. The goal of this study was to understand how the Tout from the SDD manufacturing process affected the final drug product dissolution. An L grade hydroxypropyl methylcellulose acetate succinate (HPMC-AS LG) based model SDD formulation containing a BCS class II (poor solubility in aqueous solution and high permeability) API with pKa ∼9.5 was selected for this study. The SDD material contains 20% API and 80% HPMC-AS. The SDD was manufactured at different Tout. The drug product tablet contains ∼64% of the SDD and other commonly used solid dose excipients such as microcrystalline cellulose (Avicel®), croscarmellose sodium and magnesium stearate. The drug product manufacturing process consisted of blending, roller compaction, tablet compression and film coating steps. Conventional physical characterizations on the SDD material such as particle size and bulk/tap density measurements were conducted to provide the basic information on the SDD material properties. In addition, advanced imaging techniques were used for SDD particle characterizations in order to understand what material properties may affect the drug product dissolution. These techniques provide powerful visualization and characterization of SDD particle morphology in the literature.17, 18, 19 In this study, Scanning Electron Microscopy (SEM) and X-ray Computed Tomography (XRCT) imaging techniques as well as X-ray Photoelectron Spectroscopy (XPS) surface analysis were employed to aid the SDD particle characterizations and comparison. Dissolution testing was performed on the drug product tablets and SDD powder made at different Tout to understand the linkage from manufacturing Tout, SDD material morphology to dissolution rate. Dissolution of the drug product tablets was performed with USP II (paddle) dissolution apparatus. For SDD powder dissolution comparison, an intrinsic dissolution device and modified USP I (basket) dissolution apparatus were used. UV fiber optic was also employed to monitor the real time dissolution signal. Furthermore, the SDD materials were physically separated by density into fractions with enriched dense, solid particles and light, hollow particles for dissolution comparison. To our knowledge, no such studies of this nature were found in the literature.

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Materials

Model compound MK-A drug substance was synthesized by Merck & Co., Inc., Rahway, NJ. HPMC-AS LG  (Shin-Etsu produkt) LG was purchased from Shin-Etsu (Tokyo, Japan). Model SDD (MK-A spray-dried with HPMC-AS) was made using a PSD-2 pilot scale spray dryer (batch size < 50 kg). The SDD contained 20% (by weight) MK-A and 80% (by weight) HPMC-AS. The spray-dry solution contained 88/12 w/w% acetone/water solvent and 7 w/w% solids.

Guangyu Ma, David Lavrich, Mark Schaefer, Hanmi Xi, Steve Liang, Julie Novak, Mark Mowery, Understanding the impact of spray drying temperature on the dissolution behavior of a HPMC-AS spray dried formulation, Journal of Pharmaceutical Sciences, 2026, 104322, ISSN 0022-3549, https://doi.org/10.1016/j.xphs.2026.104322.

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