June 24, 2024

Using Advanced Strategies for Identifying Large Molecule Dose Formulations


At first glance, dose formulation services may appear to be fairly ubiquitous across the industry, although there are many nuances that can make or break the client experience. Here, Dr. Ali with Ascendia Pharmaceuticals shares how Ascendia Pharmaceutical’s services go above and beyond the industry standards.


What is Dose Formulation Analysis?


At its most basic level, dose formulation identification is to determine a formulation’s composition, taking into consideration the excipients and the drug(s) alike. Most often at this step the key challenge is how to identify these excipients. While it can be a very tedious, time-consuming process, most generic companies rely on reverse engineering to identify and quantify these ingredients in a given formulation, whereas Ascendia use a tailored approach to determine the formulation based on our understanding of the physical-chemical and biopharmaceutical properties of the therapeutic molecules.

Ascendia’s Identification First Approach


One of the key factors that sets Ascendia apart is its approach to dosage form identification. Ascendia works to identify the dose first. Clients can approach Ascendia with their APIs (active pharmaceutical ingredients), and they’ll know exactly what ingredients are used in those formulations.

An example of this in practice would be a client who might be in the process of developing a parental formulation of a drug that’s already been marketed-. They know exactly what excipients to use, since they can see excipients approved for these drug products by their – drug labels or package inserts, thus eliminating the need for a tedious reverse engineering process. One particular advantage of parental formulations of approved drugs is that many of the ingredients have already been quantified and used in specific ratios.

However, if a client is looking into an oral or topical formulation, the reverse engineering process will need to be utilized to find out the compositions of each ingredient used, a process that takes time and resources to accomplish. Moreover, if a client is looking into a novel formulation of existing drug or a formulation of new drug entity, the tailored formulation screening and development process will need to be utilized to identify the compositions.


Solving Solubility Challenges by Implementing New Technology


While finding the composition of excipients to be used can be a time-consuming process, some tools can be used to make it more manageable. Literature searches can provide valuable information, as can package inserts from the FDA drug database (Drugs@FDA). The biggest challenge that’s often faced is trying to find out what technologies have been used. For example, if a poorly soluble drug is being developed using solid dispersion technology, it could be made using either hot melt extrusion or spray drying or other, but you may not necessarily know exactly what technology has been used to market the drug product. In some references, one can figure it out. It’s not as simple as just mixing the excipient in a different composition, you need to know what technology was used, whether that was an amorphous solid dispersion, e.g hot metal extrusion, or spray dry or co-precipitation depending upon API’s physico-chemical properties.


Different technologies may be necessary depending on the solubility of the drug. A poorly soluble molecule cannot just be mixed or blended with the excipients, and compressed into a tablet, and expected to work. These poorly soluble drug molecules must effectively be converted into an amorphous state. Dispersion technologies (e.g. HME and SD) work better as they are used to break the lattice energy of the molecule to make it more soluble in an amorphous state, so that when the drug goes into water, or buffer- or in GI tract, it dissolves and becomes bioavailable.


A good example to consider is ibuprofen. Ibuprofen is a poorly soluble molecule, which although it can be simply mixed into a tablet form, employing a different technology can improve the solubility five- or ten-fold. In many instances, it’s the technology that provides the advantage and gives the formulations an edge for better bioavailability.


Expertise to Ensure Formulation Viability


Ascendia’s formulation team has expertise in the technologies available, as well as the challenges that accompany various dose formulations. The Ascendia team can screen the molecules, identify the composition of the excipients, and perform analyses on the solubility, and stability of the molecule. These are the critical attributes of a drug for determining dose form. If the drug is not soluble and will - not be absorbed well, and therefore will not be bioavailable.


No Stone Left Unturned


Ascendia takes a holistic, 360-degree point of view to ensure there are no missed opportunities. Sometimes a small, seemingly simple molecule can end up being very complex, or highly insoluble. These are just a couple of the challenges that Ascendia has the expertise to navigate, and to provide the client with the analyses to know what technologies should be applied to save time and cost, and could help move the molecules in clinical development.


Formulation development is not a simple process as often requiring several years and billions of dollars to bring a drug product to the market. Rescreening of molecules is a tedious process, but necessary for identifying the right excipients to ensure maximum solubility and stability for successful dose formulation selection.


Large Molecules Present Unique Challenges Compared to Small Molecules


Large molecules tend to be much less stable than small molecules, which presents an additional set of challenges that need to be considered. Proteins or peptides, for example, are molecules used in many polypeptide and biologics, and can be denatured or degraded. They can’t handle very harsh conditions such as high temperatures -. Similarly, nucleic acids are also limited in their temperature stability so careful handling is required for such molecules.


Small molecules, with some notable exceptions, are much more robust in their stability. They’re easy to manipulate, and they can stand high temperatures e.g. in HME (hot melt extrusion) technology and some can stand a high-shear blending without any degradation. Large molecules, on the other hand, often cannot be subjected to these - technologies since they’re so unstable. They must be handled on a much more case-by-case basis to identify the platform technologies that will be the right fit with the paradigm of the molecule structure, whether it’s Lipidsol technology, or NanoSol or Emulsol.


The Benefit of Using Ascendia for Large Molecule Dose Formulation


Ascendia offers three different enabling platform technologies for these large molecules. We can use these technologies: NanoSol, Emulsol, and Lipidsol to develop oral or parental formulations of these large, unstable, and delicate molecules. The crux of the development process is to find a stable formulation, which requires attention to detail regarding molecule structure and excipient selection. The excipients must be compatible with the molecules and at a high purity so that they don’t destroy or degrade the drug substance. Ascendia has the screening capabilities to find the best excipients for the biological properties of large molecules. Contact Ascendia today to discover how we can accelerate your project.

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