Reverse Wet Granulation for Poorly Soluble API Bioavailability
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Solution Overview
Problem
The standard one-step wet granulation process in the pharmaceutical industry is unsuitable for active pharmaceutical ingredients with poor aqueous solubility, resulting in large agglomerates, uneven erosion during dissolution, and inadequate contact between the drug and hydrophilic polymers, leading to poor bioavailability and handling issues.
Innovation Solution
The reverse wet granulation process involves mixing the API with a hydrophilic polymer to form a slurry, incorporating dry excipients, and then drying to create granules with improved flow and handling characteristics, ensuring uniform erosion and enhanced bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If standard one-step wet granulation process is used for API with poor aqueous solubility, then granules can be formed, but large agglomerates are produced and dissolution is uneven
Solution Approach 1:
The granulation process is divided into two distinct steps: first forming a slurry of API and hydrophilic polymer, then adding dry excipients. This segmentation allows the API to be thoroughly wetted by the polymer solution before excipients are incorporated, preventing large agglomerates and ensuring uniform dissolution.
Solution Approach 2:
The API is pre-mixed with the hydrophilic polymer solution to form a slurry before adding excipients. This preliminary action ensures the API is adequately wetted and dispersed, preventing poor contact and uneven dissolution that occur when excipients are added first in standard processes.
2Productivity
If standard wet granulation process is used, then granules can be produced, but inadequate wetting of drug substance occurs leading to poor bioavailability
Solution Approach 1:
The standard process adds binder solution to dry API-excipient mixture. This invention inverts the sequence by first forming a slurry of API and hydrophilic polymer, then adding dry excipients. This reversal ensures the API is thoroughly wetted by the polymer solution, improving contact and bioavailability.
Solution Approach 2:
The hydrophilic polymer acts as an intermediary that first contacts and wets the API, improving its aqueous solubility and contact efficiency. This intermediary approach ensures the API receives adequate wetting before excipients are incorporated, enhancing bioavailability.
3Speed
If particle size is reduced to improve dissolution rate, then surface area increases, but bulk flow and handling characteristics deteriorate
Solution Approach 1:
The API is combined with hydrophilic polymer to form a composite slurry that is then granulated with excipients. This composite approach allows the API to be processed in a form that maintains good flow and handling characteristics while still achieving enhanced dissolution through the hydrophilic polymer matrix.
Solution Approach 2:
The invention changes the physical state and composition parameters by forming a slurry of API and polymer before granulation. This parameter change allows the API to be processed with improved handling characteristics while the polymer matrix maintains enhanced dissolution properties.
4Speed
If spray drying is used to improve dissolution of API, then dissolution rate increases, but fine powder with poor bulk flow is produced requiring extra processing steps
Solution Approach 1:
The invention merges the dissolution enhancement function with the granulation process itself. By forming a slurry of API and hydrophilic polymer and then granulating with excipients, the process achieves both improved dissolution and good bulk flow in a single integrated operation, eliminating the need for separate spray drying and additional processing steps.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The process produces granules with improved flow and handling characteristics, leading to uniform erosion and increased bioavailability, as demonstrated by bioequivalence studies with bicalutamide tablets, achieving consistent and efficient drug release.
Implementation Method 1
the standard one-step wet granulation process also results in inadequate and uneven contact between the drug and hydrophilic polymer
Implementation Method 2
Granules can then be formed by incorporating a mixture of other dry excipients into the drug-polymer slurry
Implementation Method 3
drying the paste, to form a powder
Data Source
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Figure 2
AI summary
A granulate for use in a pharmaceutical composition and a pharmaceutical composition manufacture using the granulate, where the granule comprises an active pharmaceutical ingredient (API) having a poor water solubility (i.e., less than about 1 mg/mL) which is intimately associated with at least one pharmaceutically acceptable hydrophilic polymer. The granule optionally contains one or more pharmaceutically acceptable excipients, such as disintegrants, wetting agents, diluents, binders, lubricants, glidants, coloring agents and flavoring agents. The invention also relates to a process for preparing the pharmaceutical granulate and pharmaceutical compositions containing the granulate.