Whitepaper

Small-molecule APIs frequently present multiple solid forms, making early form selection pivotal. Inadequate understanding at this stage elevates CMC, manufacturability, IP, and clinical risks—especially under tight timelines and limited API. We outline a hypothesis-driven screening strategy that maps the polymorphic space, establishes relative stabilities (including hydrates/solvates), and generates solubility–stability data to define a robust crystallization route. Aligned with ICH and major agency expectations and designed to surface patentable forms, this approach enables confident lead-form selection, reduces late-stage conversion risk, and clarifies operating space for scale-up and tech transfer.

Mol2Med™ provides an API-sparing, 3–6-week pathway to early, data-driven solid-form and formulation decisions. Using ~500 mg–1 g of material, integrated models and targeted experiments deliver a decision-ready physicochemical profile, an objective read on oral bioavailability potential, and recommendations (salt/cocrystal vs free form; conventional vs amorphous solid dispersion). Resolving these choices at lead or candidate stage reduces reformulation cycles, conserves material, and de-risks progression to oral dosage development.

Compaction simulation emulates rotary-press conditions with minimal material and guides formulation, scale-up, and troubleshooting—linking CMAs/CPPs to CQAs to optimize tensile strength, reduce capping/sticking, and accelerate oral solid dosage development.

A concise overview of core methods (XRPD, DVS, PLM, PSD) plus four practical case studies illustrating how to diagnose amorphous vs. crystalline states, differentiate polymorphs, deconvolute agglomeration, and capture humidity-driven phase changes.

Optimizing spray drying parameters is essential for controlling particle properties and ensuring formulation robustness, enabling efficient scale-up and consistent performance of amorphous solid dispersions in modern pharmaceutical development.

Proteolysis-targeting chimeras (PROTACs) degrade proteins, expanding therapeutic reach to undruggable targets while offering selectivity and efficacy. Their poor solubility, high polarity, and large size hinder bioavailability. This article outlines solid-form strategies—polymorph screening and salt/cocrystal optimization—to enhance solubility, stability, and developability in PROTAC drug development.

Salt formation improves solubility and bioavailability for ionizable APIs, but disproportionation poses a significant stability risk. This white paper discusses key factors influencing disproportionation—such as pKₐ, pHₘₐₓ, and moisture—and presents practical strategies for risk mitigation through rational salt selection, excipient control, and formulation design. Case studies illustrate how these principles are applied in development.

In 2024, the U.S. Food and Drug Administration (FDA) approved a total of 50 new drugs, including 34 new molecular entities (NMEs). Among these, 28 are small molecule drugs. In this paper, An analysis of their administration routes and dosage forms will be discussed.

Strategic partners, Crystal Bio and CATUG, combined efforts to evaluate the effects of mRNA-LNP integrity during international shipping to compare data between shipping sites for: 

ꔷ Size with distribution 

ꔷ Encapsulation 

ꔷ Purity

Following the successful launch of CQAs in LNP-mRNA Modality, we continue the series with CQA in ADC Modality. This white paper discusses: ADC components, ADC-related CQA, Impact on safety and efficacy.

Antibody drug conjugates (ADC) are typically composed of an antibody chemically attached with small molecule drugs as payload through linkers. D0 refers to an antibody conjugated with no drug (0 payload or naked antibody).

Hot melt extrusion (HME) technology is widely used in the development of amorphous solid dispersions; polymers play essential roles in the preparation of polymer-drug amorphous solid dispersions. This paper explores the criteria for selecting suitable polymers for the preparation of amorphous solid dispersions using hot melt extrusion.

How Crystal Pharmatech, a leading CRDMO, leverages GastroPlus® to guide small molecule development and manufacturing decisions.

How can physiologically-based pharmacokinetic (PBPK) modeling maximize ADME performance and identify a path forward for GLP Tox and FIH formulations?

With an ever-increasing interest in designing mRNA-based vaccines, mRNA-Lipid nanoparticles (mRNA-LNP) formulation is a relatively new modality. This white paper series first discusses numerous quality attributes with influencing potency, stability, toxicity, and risk assessment relevant to mRNA-LNP modality.

In the previous article, we explored common techniques for characterizing ASD. After characterization, it is essential to evaluate ASD’s solubility, dissolution rate, and stability to determine its suitability for further development. This section will focus on the comprehensive evaluation of ASD.

The characterization of ASD commonly employs various analytical techniques, including XRPD, DSC, PLM, SEM, IR, RM, and ssNMR. These methods provide essential insights into the physical and chemical properties of ASD, facilitating an understanding of its behavior under various conditions.

In the biomanufacturing industry, Critical Quality Attributes (CQA) are essential standards that must be met before biopharmaceuticals or medical devices can be released for patient use. As a fundamental component of CQA for a Drug Product (DP), manufacturers are required to conduct rigorous testing to ensure compliance with regulatory limits for adventitious agents.

On March 14, 2024, Madrigal Pharmaceuticals announced FDA approval of Resmetirom (Redzdira). This pivotal milestone underscores the critical importance of innovative therapies in addressing longstanding medical challenges.

In 2023, the FDA's Center for Drug Evaluation and Research (CDER) approved a total of 55 new drugs, which included 38 new molecular entities, of which 30 were small molecule drugs. In this paper, the situation of polymorph patent application of 30 small molecule new drugs will be discussed.

Spray drying techniques are extensively employed in developing formulations for drugs with low solubility, largely due to their well-established scalability from small-scale experiments to large-scale commercial production, aligning with Good Manufacturing Practice (GMP) standards.

In the development of a robust and effective Amorphous Solid Dispersion (ASD) formulation, it is imperative to rigorously evaluate several key factors, encompassing drug-polymer miscibility, drug solubility in the polymer, drug-polymer interactions, manufacturing processes, and storage conditions.

HME is recognized as an optimal and efficient technique for manufacturing ASD, characterized by its continuous processing, increased production efficiency, reduced energy consumption, and environmental sustainability, particularly suitable for the preparation of formulations for drugs with poor solubility.

Depending on the approach used to disturb the crystalline lattice, ASD preparation methods can be broadly classified into two categories: solvent-based methods and melting or fusion methods.

ASD, a formulation technology, operates on the fundamental principle of blending drug molecules with suitable polymer-carriers. This process ensures the uniform dispersion of drug molecules within the polymer matrix, resulting in the formation of an amorphous solid solution or suspension.

Various widely employed method for solubility enhancement, including salt formation, polymorphism, particle size reduction of active pharmaceutical ingredients (APIs), the preparation of amorphous solid dispersions (ASD), and the addition of cyclodextrins or surfactants.

Compare different analytical techniques (ssNMR, XPRD, DSC) for detection and characterization of crystalline phase impurities in spray-dried dispersions (SDD) using the model compound Triamcinolone.

API phase and formulation should be able to reach desired exposures and have adequate chemical and physical stability for GLP toxicology and first in human (FIH) studies. Any changes to form or formulation will incur significant time and resource penalties.

Integrating the efforts of drug-discovery scientists, material scientists and formulation specialists earlier in the discovery process can reduce drug-development timelines, risk and overall costs and provide other competitive advantages.

A pharmaceutical salt is a crystalline form that is commonly used to change pharmaceutical properties, such as solubility, dissolution, stability, or bioavailability. Salts can be used in early development for animal pharmacokinetic studies, in human clinical trials, and in marketed products.

Solid form is a general term that refers to both crystalline and amorphous materials. The solid form will impact active pharmaceutical ingredient (API) development properties such as solubility, dissolution rate, stability, hygroscopicity, and bioavailability.

Batch-to-batch variability during the crystallization of active pharmaceutical ingredients (API) can have a profound impact on both safety and efficacy of the final drug formulation, and direct business and cost implications for both the API manufacturer and downstream drug-formulation partners.

A pharmaceutical co-crystal is a crystalline form that can be used to change pharmaceutical properties, such as solubility, dissolution, stability, hygroscopicity, or bioavailability. Co-crystals can be used in early development for animal pharmacokinetic studies, in human clinical trials, and in marketed products.

Amorphous solid dispersions combine the increased solubility of an amorphous material and the improved physical stability of more stable solid forms. Amorphous solid disperions can be used in early animal studies and in marketed products.