Characterizing an API’s different salt forms and polymorphs is an essential drug development task. The successful preclinical assessment and product development can significantly depend on these forms. Selecting salt forms and conducting polymorphic screening is crucial in drug development, as it significantly impacts formulation development and overall drug success.

Why is salt form selection important?

Salt screening and selection are critical for the successful development of small-molecule drug candidates. Salt modification allows chemists and formulators to alter the physical and chemical properties of a drug molecule, such as solubility, stability, hygroscopicity, and flow properties. This modification can improve the active pharmaceutical ingredient (API) and drug product manufacturing processes, extend the drug’s shelf life, and even enhance the end-product’s efficacy and safety.

Approximately 50% of small-molecule drugs on the market are developed as salt forms. Hydrochloric salts, for example, salt forms are used for both Zantac® (heartburn relief) and Zyrtec® (allergy relief).

Can salt form selection eliminate the need for formulation development to enhance bioavailability?

Partially. While salt forms are indeed selected to overcome development challenges, they serve multiple purposes beyond purification or isolation of the API. A salt form is an effective approach to enhance the solubility and bioavailability of poorly soluble molecules. It simplifies and accelerates the formulation development process, allowing the use of API powder or simple blends in capsules for clinical trials. Furthermore, it permits the use of a conventional tablet or capsule formulation for the commercial product. Nonetheless, salt forms do not replace the need for formulation development, despite making the formulator’s job more manageable.

What advantages does Renejix offer regarding salt selection, polymorph screening, and automation?

Renejix’s cutting-edge technology, seasoned scientists, and expertise set us apart from the rest. We boast a highly automated high-throughput screening platform and workflows combined with a state-of-the-art system  equipped with advanced analytical capabilities, data analysis software, and top-notch automation.

We supported the development of nearly 20 compounds every year across a wide range of therapeutic areas. We specialize in tackling compounds with solubility and chemical stability challenges or those that are notoriously difficult to crystalize and isolate. Our flexible and customizable workflow can be tailored to accommodate program requirements, material availability, and budgetary constraints, completing most screens within five weeks, a timeline that’s significantly faster than industry standards. Our team of scientists boasts advanced degrees and 25+ years of experience, guaranteeing excellent results.

Why it’s crucial to screen for polymorphs?

Polymorphs are distinct crystal structures of a molecule that exhibit unique physicochemical properties, such as solubility and chemical stability, due to different arrangements or conformations of molecules in the crystal lattice. This phenomenon occurs when a compound can crystallize in multiple ways, resulting in different solid forms with varying properties. 

Polymorph screening is imperative in pharmaceutical and materials science industries to identify and characterize different polymorphs, hydrates, and solvates, and determine their thermodynamic relationships. This process helps researchers select the most appropriate polymorph for development, considering factors like bioavailability, manufacturing processes, and stability.

what instruments are used for polymorph screening?

A variety of techniques are employed to identify and assess different polymorphs. Optical microscopy allows for visual examination of crystal morphology, while powder X-ray diffraction (PXRD) provides valuable information about the crystal structure and can differentiate between different polymorphs.

Thermal analysis techniques, such as differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), help determine the melting points, phase transitions, and thermal stability of polymorphs. Vibrational spectroscopy methods like infrared (IR) and Raman spectroscopy can identify characteristic molecular vibrations, aiding in polymorph identification.

Additionally, dynamic vapor sorption (DVS) is used to assess the moisture absorption profile of different polymorphs. This technique measures the amount of moisture absorbed or desorbed by a sample as a function of humidity, providing insights into the stability and formulation considerations.

data driven decisions: How can polymorph screening and selection expedite drug development?

Polymorph screening and selection play a crucial role in accelerating drug development by facilitating the identification of the most appropriate polymorph for formulation. The outcomes of this process have significant implications for key decisions at various stages of the drug development pipeline.

During the initial phases of drug development, polymorph screening is essential in identifying all potential polymorphs that may arise during the isolation and formulation of the Active Pharmaceutical Ingredient (API). By exploring different crystalline forms, researchers can evaluate their physicochemical properties, including solubility, stability, and bioavailability. The selection of the most stable polymorph at this stage is critical to ensure the correct choice for further development.

The selection of the appropriate polymorph directly impacts pre-clinical and clinical studies. Formulating the drug with the most stable polymorph enhances its stability, dissolution rate, bioavailability and overall effect. This selection process takes into account factors such as manufacturability, formulation ease, and the desired drug delivery profile. By choosing the optimal polymorph, researchers can increase the likelihood of successful outcomes in pre-clinical and clinical studies.

Neglecting thorough polymorph screening and selection can have significant consequences. The discovery of a different polymorphic form at a later stage can lead to additional process development, reformulation, and bridging studies in toxicology and pharmacokinetics. These delays and costs can significantly impact the timeline and budget of drug development. Numerous instances of commercial product failures have been attributed to the belated discovery of different or more stable polymorphs, underscoring the importance of early screening and selection.

By expediting the drug development process, polymorph screening and selection contribute to reducing the time and resources required for optimizing formulations, conducting stability testing, and obtaining regulatory approval. Furthermore, early selection of the most appropriate polymorph helps prevent potential issues associated with the late discovery of undesired polymorphic forms.

When is the best time to conduct polymorph screening and selection tests?

The optimal time to conduct polymorph screening and selection tests is generally during the early stages of the pre-clinical phase. However, the specific timing may vary depending on the unique technical requirements, challenges, and development strategy of the drug development program.

It is crucial to complete the screening and selection process early enough to ensure the selection of the appropriate salt form that can support preclinical pharmacokinetic (PK) and toxicology studies. Additionally, it is important to identify the correct polymorph of the chosen salt to facilitate the first-time in-human study and subsequent clinical trials.

By initiating these tests early in the drug development process, the need to switch between different salt forms or polymorphic forms at later stages can be minimized. Such transitions can result in significant delays and expenses. Hence, early identification of the most suitable salt form and polymorph is advantageous to ensure continuity and avoid potential complications throughout the development journey.

Given the technical complexity and potential challenges associated with polymorph screening and selection, conducting these tests at the appropriate time allows for thorough evaluation, optimization, and formulation development based on the desired properties of the selected polymorph. This early assessment helps streamline the overall development process and supports subsequent studies and regulatory requirements.

cost & time savings from performing solid state screening selection. are the polymorh related results beneficial for regulatory filings?

Cost and time savings can be achieved through the implementation of polymorph screening and selection tests in the drug development process. While salt screening and selection are not obligatory for regulatory filings, polymorph screening is generally required in accordance with the guidelines provided by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). It specifically holds importance for the chemistry, manufacturing, and controls section of regulatory submissions.

The purpose of polymorph screening is to ensure the robustness and reliability of the manufacturing processes involved in producing the Active Pharmaceutical Ingredient (API) and the final drug product. By early identification and selection of the most appropriate polymorph, researchers can optimize the formulation, stability, and bioavailability of the drug. This proactive approach significantly mitigates the risk of encountering unexpected issues during later stages of development, ultimately reducing the need for costly changes, reformulations, and additional studies.

While there may be initial costs associated with conducting polymorph screening and selection tests, the resulting time and cost savings are substantial. By identifying and selecting the optimal polymorph early on, unnecessary delays, manufacturing complications, and expensive reformulations can be avoided.

Furthermore, the outcomes of polymorph screening and selection tests are not only beneficial but frequently required for regulatory filings. Regulatory agencies demand comprehensive information on the polymorphic forms of the API and the drug product. Demonstrating a comprehensive understanding of the polymorphic landscape and making an informed selection is crucial to ensure the stability, efficacy, and safety of the drug product for patients.

It’s highly significant is selecting salt forms and polymorphic screening and their potential impact on formulation development.

author avatar
Sridhar Gumudavelli
Sridhar Gumudavelli serves as the Vice President of Formulation R&D at Renejix Pharma Solutions, where he brings a wealth of knowledge and experience to the table. His leadership is instrumental in navigating the complex process of drug formulation, leveraging a variety of technologies to enhance drug absorption, bioavailability, and patient compliance.Sridhar’s expertise is not just limited to his hands-on experience; he is also an innovator with several patents filed under his name. These patents reflect his contributions to advancing drug delivery systems, showcasing his ability to tackle some of the most challenging problems in pharmaceutical sciences for the past 30+ years.

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