Optimizing Drug Solubility: The Role of Spray Drying in Pharmaceutical Formulation

Solubility plays a crucial role in drug absorption and therapeutic effectiveness. Poorly soluble drugs often fail during formulation, with approximately 40% of new drugs exhibiting poor aqueous solubility, thereby limiting their bioavailability. Solid dispersion technology has emerged as a viable solution to enhance solubility, dissolution, and bioavailability. One of the most effective techniques for preparing solid dispersions is spray drying.

spray-dryer-instrument.

what is a spray dryer?

Solubility plays a crucial role in drug absorption and therapeutic effectiveness. Poorly soluble drugs often fail during formulation, with approximately 40% of new drugs exhibiting poor aqueous solubility, thereby limiting their bioavailability. Solid dispersion technology has emerged as a viable solution to enhance solubility, dissolution, and bioavailability. One of the most effective techniques for preparing solid dispersions is spray drying.

Historical Background

The first known application of drying an atomized liquid stream was described in a patent by Percy in 1872. Since then, technological advancements have led to the refinement of spray drying equipment, improved understanding of fluid dynamics, and expansion of its use across multiple industries. Today, spray drying is a well-established technique in pharmaceuticals, food processing, ceramics, and chemicals.

Pharmaceutical Applications of Spray Drying

Spray drying serves multiple functions in the pharmaceutical industry, including

• Drying APIs and excipients – Ensures stability and improves handling properties.
• Granulation and encapsulation – Enhances powder flowability and protects sensitive compounds.
• Pulmonary formulations – Produce inhalable drug particles.
• Processing vitamins, peptides, and proteins – Ensures stability and bioavailability of biopharmaceuticals.

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Understanding the Spray Drying Process

 

The spray drying process consists of four fundamental stages: atomization, mixing with drying gas, evaporation, and particle separation. Each stage significantly influences the quality and performance of the final product.

1. Atomization Transforming Liquid into Droplets

Atomization is the first and most critical step in spray drying. It involves breaking down liquid feed into fine droplets, increasing the surface area for rapid solvent evaporation. Several atomization techniques exist, including:

• Rotary Atomization: Uses centrifugal force from a high-speed rotating disk or wheel
• Pressure Nozzles: Utilize high-pressure liquid forced through an orifice to create a fine spray.
• Bi-Fluid Nozzles: Use compressed air or another gas to shear the liquid stream into droplets.
• Ultrasonic Nozzles: Generate droplets through a vibrating mesh or piezoelectric actuator.

2. Mixing with Drying Gas

Once atomized, the liquid droplets mix with a heated drying gas (typically air or nitrogen). Key factors influencing this stage include:

• Temperature: Higher temperatures enhance drying but can degrade thermosensitive materials.
• Humidity: Lower humidity improves solvent evaporation rates.
• Flow Rate: Influences residence time and drying efficiency.

3. Evaporation and Drying

Solvent evaporation leads to the formation of solid particles. Important considerations include:

• Solvent Type: Organic solvents require closed-loop systems with nitrogen and condensers.
• Solids Content: Higher solids content results in larger particles and reduced drying efficiency.
• Feed Viscosity and Surface Tension: Affect atomization efficiency and droplet formation.

4. Particle Separation and Collection

Once dried, solid particles must be separated from the gas stream. This is typically achieved using:

• Cyclone Separators: Utilize centrifugal force to separate particles based on density differences.
• Bag Filters: Capture finer particles that escape the cyclone.

https://youtu.be/DjTollRHOjw?si=fBH-7lII61cI-hdK

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Spray drying of pure poorly water-soluble drugs

Spray Drying of Pure Poorly Water-Soluble Drugs Spray drying is a widely used technique for poorly water-soluble drugs, primarily to produce amorphous materials. It is also increasingly preferred for particle engineering, including size reduction and surface area enhancement, as well as for drying nanosuspensions to create nanoparticle or nanocrystalline dispersions of such drugs.

This method works effectively when the drug is soluble in volatile organic solvents or solvent mixtures. However, the solid-state form of the final product is mainly determined by the drug’s chemical properties, and the outcome can range from amorphous forms to partially crystalline mixtures, or crystals with imperfections and metastable structures.

Amorphization in Spray Drying

• Fully Amorphous Forms: Some drugs, such as indomethacin and itraconazole, result in stable amorphous forms upon spray drying.
• Minimal Amorphization: Other drugs, like naproxen, show limited transition to the amorphous state.

The ability of a drug to transition into an amorphous state depends largely on its glass-forming capacity, which is influenced by its molecular structure, as well as, to a lesser extent, by the preparation method.

Glass-Forming Capacity

The ability to transition into an amorphous state is influenced by:

• Preparation method (to a lesser extent)
• Molecular structure

Physical Stability of Amorphous Forms

A critical challenge for poorly soluble drugs in their amorphous state is maintaining physical stability against recrystallization.

• Glass Transition Temperature (Tg): A key parameter for stability, as it helps predict the stability of the material against re crystallization Below Tg, the material remains in a less mobile, glassy state, reducing re-crystallization risk.
• When the temperature is below Tg, the material remains in a glassy, less mobile state, making it more resistant to re-crystallization compared to the higher-mobility super-cooled liquid state that occurs above Tg. The stability of amorphous forms is typically maintained when stored at temperatures around Tg – 50°C, which corresponds to the Kauzmann temperature, where the material’s translational and rotational motions essentially cease over relevant time scales

Examples:

• Spray-dried paclitaxel exhibits a significant increase in solubility due to the amorphous form, compared to the crystalline dihydrate and anhydrate forms obtained through precipitation and colloid formation.
• Spray-dried amorphous celecoxib shows improved surface energy, wettability, and polar surface distribution, all of which are enhanced relative to its pure crystalline form.

Advantages of Amorphous Solid Dispersions (SDDs)

Over the past three decades, the development of amorphous solid dispersions (SDDs) has gained significant momentum in improving the oral bioavailability of poorly water-soluble drugs.

Spray drying is a preferred method due to its:

• Continuous manufacturing
• Scalability
• Cost-effectiveness

Key Components for SDD Formulation

key components for formulating SDDs: carriers -solvents- additives

Selection of Drug Candidates

The ideal drug candidates for SDDs are selected based on their physicochemical properties:

• Melting point/enthalpy
• Solid-state thermal stability
• Ionization constant
• Hydrogen bonding capability (donor/acceptor ability)
• Solubility and interaction parameters
• Partition coefficient

These properties, along with the desired downstream processing characteristics, guide the selection of suitable drugs for amorphous dispersion formulation.

Thermolabile molecules are particularly suitable for amorphous dispersion through solvent-based processes, such as spray drying, as compared to melt-based methods. However, the process requires the drug to be soluble in a volatile organic solvent or a mixture of solvents to ensure efficient spray drying and commercial feasibility.

Selection of Carriers

Carriers play a crucial role in preventing crystallization and maintaining solubility:

• Hydrophilic Polymeric Carriers: they serve as crystallization inhibitors as they reduce molecular mobility of the amorphous drug thus preventing recrystallization and maintaining enhanced solubility during in vitro dissolution and after oral administration in the gastrointestinal tract.
• Solubility Considerations: To ensure successful formulation, both the drug and polymer need to be soluble in a common volatile solvent or a mixture of solvents. However, creating a suspension of the drug and polymer in the solvent may result in phase separation or partial crystallization, which can negatively affect the homogeneity and physical properties of the final product.

Therefore, it is essential to carefully consider the impact of solution-state chemistry on the molecular, particulate, and bulk properties of the final SDD.

Molecular-Level Interactions and Miscibility

• Achieving molecular-level homogeneity between the drug and polymer is key for stability.
• Strong intermolecular interactions (hydrogen bonding, electrostatic, or hydrophobic interactions) improve solid solubility and reduce recrystallization risk.

Binary vs. Ternary SDD Systems

SDDs are typically formulated as binary or ternary systems:

In practice, SDDs are often formulated as binary or ternary systems. A ternary system typically includes a surfactant or additional excipients such as glidants, binders, or disintegrants to improve the downstream processing and the dissolution rate of poorly soluble drugs.

• Binary System: Drug + polymer
• Ternary System: Drug + polymer + excipient (e.g., surfactants, glidants, binders, or disintegrants)

The general trend in SDD formulation has been to combine a drug, polymeric carrier, and additives to optimize the physical structure and enhance in vitro dissolution, solubility, and bioavailability.

Common Polymeric Carriers for SDDs

Recent research by Shah et al. (2012) has compiled a list of commonly used polymeric carriers for the preparation of SDDs, highlighting their physicochemical properties. Some key examples of polymers and poorly soluble APIs formulated as SDDs include:

• Cellulose derivatives
• Polyvinylpyrrolidone (PVP)
• Hydroxypropyl methylcellulose (HPMC)
• Polyethylene glycol (PEG)
• Eudragit® polymers

Each of these carriers has specific advantages in stabilizing the amorphous form and improving dissolution rates, wettability, and bioavailability.

Cellulosic Derivatives

Cellulose, a natural polymer, is an unbranched polysaccharide composed of glucose monomer units connected via 1,4-glycosidic β-linkages. In the pharmaceutical industry, cellulose is commonly used as a semi-synthetic excipient, modified through alkyl or hydroxyl alkyl substitutions, or as esters of cellulose derivatives. Some common cellulosic derivatives include:

• Methyl Cellulose (MC)
• Ethyl Cellulose (EC)
• Hydroxypropyl Methyl Cellulose (HPMC)
• Hydroxypropyl Cellulose (HPC)
• Cellulose Acetate Phthalate (CAP)
• HPMC Phthalate (HPMC-P)
• HPMC Acetate Succinate (HPMC-AS)

The physicochemical properties of these cellulosic derivatives vary significantly depending on the degree of substitution.

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Hydroxypropyl Methyl Cellulose (HPMC) in SDDs  

HPMC is one of the most commonly used cellulosic stabilizers for SDDs of poorly soluble drugs. It is available in various grades, characterized by different substitution levels of methyl (16–30%) and hydroxypropyl (4–32%) groups on the cellulose backbone. This variation gives HPMC a broad range of physicochemical properties, such as viscosity, solubility, and surface activity.

Example:

HPMC 2906: Contains 29% methyl and 6% hydroxypropyl substitution. It is a water-soluble polymer that exhibits thermal gelation in aqueous solutions.

• For spray drying of SDDs, HPMC is not soluble in many volatile solvents like dichloromethane (DCM), acetone, or methanol, Therefore, binary solvent systems (e.g., DCM with alcohol) are often necessary for the spray drying process.

• The hydroxypropyl group in HPMC acts as a hydrogen bond donor, while the methoxyl group weakly accepts hydrogen bonds. This makes HPMC particularly effective in stabilizing hydrogen bond-accepting drugs in the SDD formulation.

Study Example:

A study on tolbutamide formulated with HPMC using spray drying showed a significant improvement in dissolution rate and extent compared to an aqueous suspension method..

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Hydroxypropyl Methyl Cellulose Acetate Succinate (HPMC-AS)

HPMC-AS is another cellulosic derivative widely used in SDD formulations due to its versatility, particularly its ability to solubilize poorly water-soluble drugs in common spray-drying solvents like methanol and acetone.

• HPMC-AS is ionizable across a physiologically relevant pH range, making it suitable for enhancing bioavailability in the gastrointestinal tract.

Key Advantages of HPMC-AS Over HPMC:

• Friesen et al. (2008) conducted a comprehensive study on over 100 poorly soluble drugs formulated with HPMC-AS, showing its superior formulation processability and physical stability.

• The amphiphilic nature of HPMC-AS, with its combination of hydrophobic and hydrophilic functionalities, allows it to effectively interact with poorly water-soluble drugs, maintaining a colloidal nano-structure during dissolution

Example:

• Griseofulvin formulated with HPMC-AS remained physically stable for 19 months at 85% RH, while the pure drug recrystallized upon spray drying.

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Vinyl polymers

Vinyl polymers have become a significant class of excipients for the preparation of amorphous solid dispersions (SDDs) aimed at enhancing the solubility of poorly water-soluble drugs. These polymers are typically synthesized via free radical polymerization from alkene derivatives, and the resulting polymers vary significantly depending on the chemical structure of the side chains.

Among the most commonly used vinyl polymers for SDDs is poly(N-vinylpyrrolidone) (PVP).

poly(N-vinylpyrrolidone) (PVP)

Also known as povidone, PVP is a hydrophilic polymer frequently used as a carrier for SDDs.

It is known for its good solubility and chemical stability in a wide range of solvents like alcohols, chloroform, and esters.

PVP is available in different molecular weights:

PVP K12 (lower molecular weight)

PVP K90 (higher molecular weight) – Higher viscosity, making it harder to process via spray drying.

Consideration: PVP is hygroscopic, meaning it absorbs moisture, which may affect the physical stability of SDDs.

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 Solvent Systems for SDD Preparation

Selecting the appropriate solvent system is crucial for achieving the desired phase structure and physicochemical properties of amorphous solid dispersions (SDDs). The main goal is to identify a solvent (or solvent mixture) that can solubilize all formulation components—API, carrier, and excipients.

Key Criteria for Choosing a Spray Drying Solvent:

1. High Solubility: The selected solvent should dissolve both the drug and the carrier at concentrations greater than 50 mg/ml to ensure the formation of a uniform feed solution.
2. Acceptable Viscosity: The solvent should allow for the formation of a feed solution with acceptable viscosity, as high viscosity can impede atomization during spray drying.
3. Low Toxicity: It is essential to choose solvents with low toxicity, particularly those classified under ICH Q3(R5) class 2 and 3 solvents.
4. High Volatility: The solvent must have high volatility to facilitate efficient solvent evaporation during the spray drying process.
5. Chemical Stability: The feed components (drug, carrier, and additives) should be chemically stable in the selected solvent, ensuring no degradation during processing.
6. Non-Combustibility: The solvent should not be combustible in the spray drying environment to avoid safety concerns.

Solvent Properties:

• Volatility: The relative volatility of a solvent determines its evaporation rate, which is crucial for achieving a sufficient yield and controlling the residual solvent content in the final product.
• Enthalpy of Vaporization: This property provides insight into the energy required for the solvent to evaporate and is important for optimizing the outlet temperature and energy consumption during spray drying.
• Viscosity and Surface Tension: These factors influence the feed atomization during spray drying and the interaction between the drug, carrier, and solvent in solution.
• Dielectric Constant and Polarizability: These parameters reflect the polarity of the solvent. Solvents with higher dielectric constants are more polar and may influence the phase structure of the resulting SDD. For example, solvents with higher polarity have been shown to enhance the amorphous content of solid dispersions, leading to higher equilibrium solubility for certain drugs.

Solvent Selection for Drug and Polymer Compatibility

• Solubility Parameter: The solubility parameter can help estimate the compatibility between the drug and carrier in the feed solution. A smaller gap between the solubility parameters of the drug and polymer tends to result in a more homogeneous solution.

Trends in Solvent Choice

Traditional Solvents: Historically, dichloromethane (DCM) was favored for spray drying due to its high volatility and strong solubilizing ability.

Modern Trends: The industry is shifting toward volatile alcohols or hydroalcoholic systems, which are more environmentally friendly, safer (less toxic), and allow for particle engineering by adjusting solvent mixtures during feed preparation.

While many poorly soluble APIs and polymer carriers are soluble in organic solvents, the increasing complexity of drug molecules being developed today often leads to solubility challenges, even in a range of traditional spray drying solvents.

Overall, solvent selection remains a critical factor in the successful preparation of amorphous SDDs, and optimizing solvent properties can significantly influence the physicochemical attributes and performance of the final product.

Conclusion:

Amorphous solid dispersions are effective for enhancing the dissolution and bioavailability of poorly soluble drugs. Key factors in their development include the selection of appropriate polymeric carriers, such as PVP and HPMC, which facilitate drug stability and solubility, and the choice of solvent systems that ensure compatibility, volatility, and safety. The interactions between drugs, polymers, and solvents play a crucial role in the formation of stable, amorphous structures. Optimizing these parameters improves drug performance and therapeutic efficacy.