caused by APIs with low melting points.

1.1 API Softening and Degradation During Processing

Causes:

• Excessive heat during dry granulation, compression, or film coating.
• Mechanical energy leading to API polymorphic transitions.
• API phase change results in inconsistent tablet hardness and weight variation.

Solutions:

• Use cooling or temperature-controlled granulation techniques (below API melting point).
• Opt for wet granulation using non-aqueous solvents to minimize heat exposure.
• Ensure that film coating temperatures do not exceed API softening points.

1.2 Poor Flowability and Compressibility

Causes:

• Low-melting APIs tend to be waxy or amorphous, leading to poor powder flow.
• High stickiness affects tablet uniformity and weight variation.

Solutions:

• Use glidants like colloidal silicon dioxide to improve powder flow.
• Incorporate high-functionality fillers such as microcrystalline cellulose (MCC) to enhance compressibility.

Step 2: Optimizing Granulation Techniques

Carefully selecting the right granulation technique can help manage low melting APIs effectively.

2.1 Wet Granulation

Best suited for heat-sensitive APIs, allowing better compressibility and particle size control.

Solutions:

• Use low-temperature drying methods such as vacuum drying or fluidized bed drying.
• Select non-aqueous granulating solvents like ethanol or isopropanol.

2.2 Dry Granulation (Roller Compaction)

Suitable for moisture-sensitive APIs but requires careful temperature control.

Solutions:

• Reduce roller compaction pressure to avoid excessive heat generation.
• Use pre-lubrication techniques to minimize friction-induced temperature rise.

2.3 Direct Compression

Preferred when API stability is a major concern.

Solutions:

• Use co-processed excipients like ProSolv® (MCC + silica) for better compressibility.
• Incorporate flow-enhancing agents such as talc or magnesium stearate.

Step 3: Controlling Compression and Tableting Parameters

Compression-induced heat can cause melting or sticking, affecting tablet quality.

3.1 Adjusting Compression Force

Solution:

• Maintain moderate compression force (5-15 kN) to avoid excessive heat generation.
• Use pre-compression steps to improve tablet density without overheating.

3.2 Minimizing Tablet Sticking

Solution:

• Use lubricants like magnesium stearate (≤1%) to reduce adhesion.
• Apply cooling air to punch surfaces to prevent API softening.

Step 4: Managing Film Coating Conditions

Film-coating involves heat and solvent exposure, which can affect low-melting APIs.

4.1 Using Low-Temperature Coating Methods

Solution:

• Use aqueous coatings with low-temperature drying (40-50°C).
• Apply anti-tacking agents like talc to prevent sticking.

4.2 Optimizing Spray Rate and Drying Air

Solution:

• Reduce inlet air temperature to prevent melting.
• Ensure gradual solvent evaporation to avoid tablet deformation.

Step 5: Stability Testing and Quality Control

Testing ensures that the formulation remains stable under manufacturing and storage conditions.

5.1 Differential Scanning Calorimetry (DSC)

Solution:

• Use DSC analysis to detect melting transitions and optimize processing conditions.

5.2 Forced Degradation Studies

Solution:

• Perform stability testing (40°C/75% RH) to assess API integrity.

Step 6: Emerging Technologies for Handling Low-Melting APIs

New techniques are enhancing the stability of heat-sensitive drugs.

6.1 Hot-Melt Extrusion (HME)

Encapsulates APIs in polymer matrices to enhance stability.

6.2 Nanoparticle-Based Formulations

Increases drug stability and reduces melting-related issues.

6.3 AI-Based Process Control

Uses machine learning to optimize temperature and compression force.

Regulatory Considerations

Ensuring compliance with regulatory guidelines is crucial for low-melting APIs.

7.1 ICH and USP Stability Requirements

Solution:

• Follow ICH Q1A guidelines for stability studies.
• Ensure USP melting point and impurity profile testing.

7.2 Bioavailability Considerations

Solution:

• Use BCS solubility classification to determine formulation strategies.

Conclusion:

Handling low melting point APIs requires a combination of optimized granulation techniques, controlled compression parameters, and specialized excipients to prevent processing challenges. By implementing cooling strategies, nanotechnology, and AI-driven process optimization, manufacturers can enhance the stability and manufacturability of heat-sensitive APIs, ensuring regulatory compliance and consistent product quality.