Amorphous Rosuvastatin Calcium Stabilization via Calcium Carbonate
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Solution Overview
Problem
The instability of amorphous rosuvastatin calcium under acidic, oxidative, and humid conditions, combined with its poor bioavailability due to its low water solubility, poses challenges in formulating a stable and effective pharmaceutical composition that maintains bioequivalence with the innovator product.
Innovation Solution
A novel pharmaceutical composition of amorphous rosuvastatin calcium is developed, utilizing an optimal ratio of insoluble stabilizing salt (calcium carbonate) and soluble filler (lactose monohydrate) along with a polyvinyl alcohol coating to enhance stability and bioavailability, ensuring bioequivalence with the originator product.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If amorphous rosuvastatin calcium is used to enhance solubility and bioavailability, then dissolution rate and oral bioavailability are improved, but physical and chemical stability deteriorates under acidic, oxidative, and humid conditions
Solution Approach 1:
The patent employs a composite formulation system combining amorphous rosuvastatin calcium with multiple excipients including calcium carbonate (insoluble stabilizing salt), lactose monohydrate (soluble filler), and polyvinyl alcohol coating. This composite approach creates a synergistic system where each component addresses specific stability issues while maintaining the bioavailability benefits of the amorphous form.
Solution Approach 2:
The patent optimizes the weight ratio parameters of calcium carbonate to lactose monohydrate (1:3 to 1:14) and controls the coating composition to achieve the desired balance between stability and solubility. By adjusting these compositional parameters, the formulation maintains amorphous stability while ensuring adequate dissolution and bioavailability.
2Stability of the object's composition
If calcium carbonate is used as an alkalizing agent to reduce hygroscopicity, then moisture uptake is reduced, but reaction with gastric HCl is slow and intragastric pH increases
Solution Approach 1:
Lactose monohydrate serves as an intermediary component that facilitates the interaction between calcium carbonate and gastric fluids. The soluble lactose matrix allows for controlled release and interaction, mediating between the need for alkaline stabilization and the requirement for adequate gastric dissolution.
Solution Approach 2:
The polyvinyl alcohol coating acts as a flexible protective shell that controls the interaction between the tablet core and the gastrointestinal environment. This coating provides a controlled release mechanism that allows gradual exposure of calcium carbonate to gastric acids while maintaining stability during storage and handling.
3Duration of action of stationary object
If the ratio of calcium carbonate to lactose monohydrate is optimized for stability, then shelf-life stability is improved, but dissolution rate and bioavailability may be compromised
Solution Approach 1:
The patent systematically optimizes the weight ratio parameters of calcium carbonate to lactose monohydrate within the range of 1:3 to 1:14. This parameter optimization ensures that sufficient lactose is present to maintain dissolution rate and bioavailability, while adequate calcium carbonate provides the necessary alkaline stabilization and hygroscopic protection throughout the shelf life.
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 composition achieves enhanced solubility, stability throughout shelf-life, and bioequivalence with the innovator product, demonstrated by similarity in dissolution profiles and pharmacokinetic parameters, with minimal impurity formation and no significant side effects, thus addressing the challenges of stability and bioavailability.
Implementation Method 1
The main advantage consists in the lowering of the hygroscopic manifestations of the active ingredient in the pharmaceutical form
Implementation Method 2
Because of the use of an insoluble alkalizing agent in the proximity of the poorly soluble drug, in order to increase the water uptake of the tablet, lactose monohydrate and a superdisintegrant were used
Implementation Method 3
The coating preferred for this invention is water based, the film former consisting of polyvinyl alcohol; it has titanium dioxide as UV absorbant and it is free of iron oxides. It provides low moisture uptake rates, excellent elasticity and adhesion and photostability
Implementation Method 4
The coating preferred for this invention is water based, the film former consisting of polyvinyl alcohol; it has titanium dioxide as UV absorbant
Implementation Method 5
An amorphous form of the active substance may be formulated to enhance the oral bioavailability of a poorly soluble drug, such as rosuvastatin calcium. The dissolution enhancement can be translated into a marked improvement in both AUC and Cmax
Data Source
AI summary
This invention concerns a novel tablet pharmaceutical composition, used for the treatment hyperlipoproteinemia, hypercholesterolaemia and atherosclerosis. The composition related to this invention comprises amorphous rosuvastatin calcium, stabilized by adding calcium carbonate in a ratio of 0,5...2:1 (w/w) and other excipients: 30...60% lactose monohydrate, 15...35% microcrystalline cellulose, 1...5% crospovidone and 0,25...5% magnesium stearate.