Simplified Formulations

Drug substance formulation is an important part of pharmaceutical development, but it is an often complex, multi-step process, which can add considerable time and expense to development programmes.

Crystec’s mSAS® (modified Supercritical Anti-Solvent) technology can offer a variety of strategies to target optimised therapeutic performance with simplified formulations.

mSAS® strategies for enabling simplified formulations

Single step, high yielding process

One of the key advantages of mSAS® is the ability to simultaneously control a range of particle properties, reducing the number of process steps from Active Pharmaceutical Ingredient (API) to the final dosage form. Conventional crystal and particle engineering processes may include multiple steps including crystallisation, harvesting, drying, milling and sieving, with each step introducing opportunities for contamination, product losses or other process failures. In contrast, mSAS® is a single step and highly reproducible process where particles are precipitated directly from solution to generate a uniform and consistent product. Furthermore, once optimised, the mSAS® process typically achieves yields in excess of 95%.

Fewer or no excipients

Formulation is often an iterative process, where excipients are added in order to mitigate the consequences of previous processing steps. For example, mechanical milling is often employed to reduce particle size and increase rates of dissolution, but unintended consequences can include the formation of amorphous regions, the introduction of static charge, and an increased propensity for agglomeration. To reduce the impact of these features on product stability and performance, a wide range of excipients are frequently used.

mSAS® allows a high degree of control over particle formation, tuning solid-state form, particle size, shape and composition, in a single step, bottom-up precipitation process. As a result, mSAS® particles have smooth, low energy surfaces, producing free flowing powders without the need for subsequent downstream formulation. For a visual demonstration comparing the flow properties of mSAS® powders with a micronised equivalent, please watch our video below:

Matching performance of complex formulations

Many marketed products are developed via complex formulation processes in order to achieve the required therapeutic performance. One example of this is Sporanox®, an itraconazole formulation prepared by a multi-step process to generate multiple layered coatings onto sugar cores, to overcome dissolution challenges. The final product contains only 20% API loading.

Crystec have applied mSAS® technology to generate micron-sized, polymer stabilised composite particles of amorphous itraconazole, with 40% drug loading, from a single step process. Furthermore, the mSAS® product can be tuned to demonstrate equivalent or superior dissolution performance to Sporonox®.

In-vivo (beagle dog) evaluation of plasma concentration over time – mSAS® itraconazole vs Sporanox®

Uniform delivery of combination products

In addition to tuning solid state and surface properties of particles, Crystec’s single-step mSAS® technology can also be applied to generate composite particles containing a uniform mixture of multiple therapeutic agents. This can prove attractive in development and manufacture of fixed dose combination products due to the ability to eliminate blend uniformity challenges. mSAS® composite particles also offer a unique opportunity to facilitate synergistic delivery of inhaled combination products, ensuring that each agent is deposited at the same site in the lung, in the correct ratio. For more information about how mSAS® can support the development of optimised inhaled therapies, please read our post.

In-particle design® formulation

By taking a “right first time” approach to product development and targeting defined particle properties from the first experiments, the need for excipients can be markedly reduced. Where the use of excipients cannot be avoided, such the incorporation of enhancing agents to support dissolution, API and excipients can be combined reproducibly with a uniform and intimate association throughout each particle. This can help to avoid the blend uniformity challenges common to conventional mixing processes, and in many cases, reduce excipient loading requirements. Overall, by combining the control and versatility of Crystec’s mSAS® technology with an in-particle design® approach, product performance can be optimised with simple formulations, streamlining manufacturing processes and reducing development timelines.

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Improving Dissolution

40% of marketed drugs and up to 90% of those in development exhibit poor solubility1. mSAS® provides different ways to address this challenge, including through increasing surface area, reducing agglomeration, new solid-state forms, co-crystals or stabilised amorphous forms of drug molecules.

Optimised Inhaled Therapies

mSAS® enables the design of drug particles of precise size and shape, that aerosolise even in patients who may struggle to breathe. As well as treating lung disease, inhaled therapies can be designed to enter the bloodstream, providing opportunities for fast onset and an alternative to painful injections.

Enhancing Stability

Chemical and physical stability is vital to ensure that therapeutics can be manufactured, stored, transported and administered to patients without a loss of efficacy or safety. mSAS® enables manufacture of highly pure, residue-free drug particles, capable of resisting moisture, and able to withstand higher temperatures.

Simplified Formulations

Formulation is often a complex, multi-step process, adding considerable time and cost to development. The mSAS® process involves a single step, and enables design of particles which contain all the components required for a medicine to perform, reducing the need for downstream processing.

Biomolecule Processing

Biotherapeutics such as peptides, proateins, antibodies and oligonucleotides are often delicate and easily damaged. mSAS® provides a gentle way to process biomolecules as free-flowing powders, retaining high levels of activity, reducing cold chain and enabling easier reconstitution.

Natural Products

Natural products are often highly complex and conventional approaches to their extraction, purification and formulation can be inefficient and often result in a poor-quality product. mSAS® simplifies production of natural products, allowing fine tuning of the components of a medicine and improvements in quality and consistency.

Green Manufacturing

Improvements in human health should not come at the cost to the planet, yet traditional approaches to medicines manufacturing carry a high environmental burden. mSAS® enables the production of medicines with lower waste, reduced emissions, using less solvent, and greatly improved energy efficiency.

Intellectual Property

Innovation in medicines development often requires robust protection of intellectual property (IP). The mSAS® process provides numerous opportunities to enhance IP, whether through novel solid-state forms, improved formulations or new routes of delivery.