Molindone Formulation Stability via Low Water Content and Acidifiers

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Solution Overview

Problem

Molindone salts, such as molindone hydrochloride, are not compatible with many commonly used pharmaceutical excipients, leading to significant degradation and instability in formulations, making it challenging to create stable immediate release (IR) and modified release (MR) formulations.

Innovation Solution

Stable IR and MR formulations of molindone are achieved by maintaining a low water content of less than 5% by weight in the formulation and using specific stabilizing excipients like acidifiers and hydrophobicity inducing agents, which include fumaric acid, citric acid, and magnesium stearate, to prevent degradation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of manufacture

If molindone salts are formulated with commonly used pharmaceutical excipients, then the formulation can be manufactured with standard excipients, but the molindone degrades significantly and becomes unstable

Engineering Contradiction:

Improveformulation manufacturingVSAvoidformulation stability

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The patent changes the chemical environment parameters by incorporating acidifying agents to maintain pH below 6.0, and controls moisture content below 5%, transforming the formulation conditions to prevent degradation while maintaining manufacturability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces acidifying agents (citric acid, fumaric acid, tartaric acid) as intermediary substances that mediate between the molindone salt and other excipients, preventing direct harmful interactions and stabilizing the formulation

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If water content is increased to improve dissolution and absorption, then bioavailability may improve, but the molindone degrades faster

Engineering Contradiction:

Improvedrug absorption rateVSAvoiddrug stability

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent optimizes the water content parameter to a specific range (below 5%) and maintains acidic pH conditions, creating a stable environment that prevents degradation while still allowing sufficient dissolution for absorption

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates a composite formulation system combining molindone salt with acidifying agents and hydrophobicity-inducing excipients, where the combined effect provides both stability and controlled dissolution

Inventive Principle:

Principle #40Composite materials

3Speed

If immediate release formulation is used for rapid absorption, then therapeutic effect is achieved quickly, but the drug is eliminated rapidly with short half-life

Engineering Contradiction:

Improveabsorption speedVSAvoidtherapeutic duration

Core Design Contradiction:

SpeedVSDuration of action of moving object

Solution Approach 1:

The patent divides the single dose into multiple release phases using combinations of immediate release, extended release, and delayed release mechanisms, providing both rapid initial effect and sustained therapeutic coverage

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent implements pulsatile release patterns where the drug is released in periodic phases - initial rapid release followed by sustained release - matching the therapeutic needs throughout the dosing interval

Inventive Principle:

Principle #19Periodic action

4Reliability

If multiple dosing throughout the day is used to maintain therapeutic levels, then continuous coverage is achieved, but patient compliance and convenience decrease

Engineering Contradiction:

Improvetherapeutic coverageVSAvoiddosing convenience

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent segments the dosing regimen into a single daily dose that incorporates multiple release mechanisms, eliminating the need for multiple administrations while maintaining continuous therapeutic coverage

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent creates a multi-functional dosage form that combines immediate release, extended release, and delayed release capabilities in a single tablet, providing comprehensive therapeutic coverage throughout the day

Inventive Principle:

Principle #6Universality (Multi-functionality)

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 use of low water content and stabilizing excipients results in stable molindone formulations that maintain therapeutic blood concentrations for 4 to 24 hours, providing effective treatment for CNS disorders like impulsive aggression and aggression with reduced degradation issues.

Implementation Method 1

using specific stabilizing excipients like acidifiers and hydrophobicity inducing agents, which include fumaric acid, citric acid, and magnesium stearate, to prevent degradation

Methodology Applied

Scientific EffectHydrophobicity inducing: Hydrophobe

Data Source

PatentUS20210322429A1Stabilized formulations of CNS compounds

Publication Date: 2021.10.21 SUPERNUS PHARMACEUTICALS INC

AI summary

Formulations of molindone having superior stability and methods of administering same are provided. The formulations may be immediate, modified, or otherwise delayed release formulations of molindone.