Hydrochlorothiazide Oral Suspension Formulation
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Solution Overview
Problem
Current hydrochlorothiazide formulations, particularly solid dosage forms, face challenges such as instability, contamination risks, and poor bioavailability, especially in pediatric and geriatric populations, and patients requiring feeding tubes, leading to inaccurate dosing and reduced therapeutic effectiveness.
Innovation Solution
A stable oral liquid composition of hydrochlorothiazide with reduced salamide content, formulated as a powder for suspension, containing 3-5% w/w hydrochlorothiazide, a thickening agent, and pharmaceutically acceptable excipients, which, when reconstituted, maintains stability and uniformity for long-term use and is suitable for administration via feeding tubes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If hydrochlorothiazide is formulated as solid dosage forms (tablets, capsules), then manufacturing and storage are simplified, but stability deteriorates due to hydrolytic degradation and contamination risks
Solution Approach 1:
The patent changes the physical state parameter from solid to liquid formulation, and adjusts pH parameters to 3.5-5.5 to minimize hydrolytic degradation. This parameter change resolves the contradiction by maintaining stability while enabling simplified manufacturing through direct liquid formulation without compression or coating steps.
Solution Approach 2:
The patent introduces pH buffers and stabilizing excipients as intermediaries that mediate between the drug molecule and environmental factors causing degradation. These intermediaries maintain optimal pH conditions and protect against hydrolysis, resolving the stability issue while keeping the formulation manufacturable.
2Ease of operation
If hydrochlorothiazide tablets are crushed to prepare suspensions, then administration to pediatric and geriatric patients is facilitated, but contamination risk increases and dosing accuracy deteriorates
Solution Approach 1:
The patent performs preliminary action by pre-formulating the drug as a stable liquid suspension with accurate dosing concentrations. This eliminates the need for crushing and manual preparation at the point of administration, thereby maintaining dosing accuracy and reducing contamination risk while facilitating easy administration to patients with swallowing difficulties.
3Manufacturing precision
If hydrochlorothiazide is formulated in aqueous solution, then bioavailability is improved, but stability deteriorates due to hydrolytic degradation
Solution Approach 1:
The patent changes the pH parameter to an acidic range (3.5-5.5) which kinetically stabilizes the hydrochlorothiazide molecule against hydrolytic degradation while maintaining aqueous solubility. This parameter optimization resolves the contradiction by achieving both improved bioavailability through aqueous formulation and enhanced stability through pH control.
Solution Approach 2:
The patent converts the potentially harmful effect of water (causing hydrolysis) into a benefit by using aqueous formulation for improved bioavailability, while counteracting the degradation through pH control. The water that would normally cause degradation is now part of a stabilized system where pH conditions prevent hydrolysis, achieving both solubility and stability.
4Ease of operation
If gelatin capsules are used for hydrochlorothiazide, then dosage delivery is simplified, but compatibility deteriorates due to moisture sensitivity and excipient interactions
Solution Approach 1:
The patent extracts the drug from the gelatin capsule delivery system and reformulates it as a direct liquid suspension. This removes the compatibility issues between gelatin, moisture, and excipients while maintaining simplified dosage delivery through ready-to-administer liquid form with accurate dosing concentrations.
Data Source
AI summary
Disclosed herein is a powder for oral suspension and a reconstituted product thereof comprising highly pure hydrochlorothiazide, which is useful for treating hypertension and edema.