Orforglipron Spray-Dried Dispersion (Orforglipron SDD)

Product Overview

Orforglipron (development codes LY3502970/OWL-833) is the world’s first approved oral non-peptide small-molecule GLP-1 receptor agonist; it binds allosterically to the transmembrane pocket of the GLP-1 receptor, shows biased agonism toward the cAMP pathway, and recruits almost no β-arrestin.

Why SDD is needed: Orforglipron is a highly lipophilic, large-molecular-weight (883 Da) compound (calculated XLogP3 6.8, topological polar surface area 144 Ų); its calcium salt is explicitly described in the US prescribing information as “insoluble in water,” and the free acid is likewise insoluble in water and insoluble in ethanol, being soluble only in organic solvents such as DMSO, DMF, and methanol—a typical solubility-limited-absorption molecule. Spray-dried dispersion (SDD) is the most mainstream preparation process among amorphous solid dispersions (ASD): the API and carrier polymer are co-dissolved in a volatile solvent and atomized, then instantly dried in a heated chamber; the rapid evaporation of solvent “kinetically traps” the API at the molecular level and locks it within the polymer matrix, forming an amorphous glass solution. This form eliminates the lattice energy barrier, dissolves rapidly upon entering the gastrointestinal tract to form a supersaturated solution, while the polymer inhibits recrystallization through hydrogen bonding, increased system viscosity, and reduced molecular mobility, prolonging the maintenance of supersaturation and thereby enhancing absorption flux across the gastrointestinal epithelium and in vivo exposure.

Carrier selection: This product uses copovidone (vinylpyrrolidone-vinyl acetate copolymer, commonly the PVP/VA64 grade) as the carrier. Review literature notes that copovidone is widely used in ASDs owing to its excellent processing properties and lower hygroscopicity than povidone homopolymer; among the 48 ASD products approved by the FDA from 2012 to 2023, copovidone was the most commonly used carrier polymer (about 49%), spray drying was the most commonly used preparation process (about 54%), and such products mainly target BCS Class II and IV drugs. Copovidone has a glass transition temperature of about 100–111 °C and a degradation temperature above 230 °C, making it suitable for spray-drying processing of heat-sensitive molecules.

Relationship to the hemicalcium salt form: CAS 2212020-52-3 for this product corresponds to orforglipron free acid (PubChem CID 137319706); the previous entry, 3008544-96-2, is its hemicalcium salt monohydrate. In the marketed formulation Foundayo tablets, the oxadiazolone exists as the deprotonated calcium salt, and the strength is expressed as orforglipron free acid.

Technical Specifications

• Standards: CHP/USP/EP
• Specification: 30% API + 70% copovidone (PVP/VA64); dosage form is a spray-dried dispersion (SDD)
• CAS Number: 2212020-52-3 (orforglipron free acid; the hemicalcium salt monohydrate is 3008544-96-2)
• Molecular Formula: C₄₈H₄₈F₂N₁₀O₅ (free acid; the hemicalcium salt monohydrate is C₄₈H₄₈F₂N₁₀O₅·½Ca·H₂O)
• Molecular Weight: 883.0 g/mol (PubChem, Cayman; MCE and Selleck state 882.96/882.97 respectively); monoisotopic mass 882.3777 Da; the hemicalcium salt monohydrate is 921.02 g/mol
• Appearance: White to off-white spray-dried powder (the free acid API itself is a white to off-white/pale yellow solid)
• API Purity (HPLC): ≥ 99.0%; labeled API content in the SDD is 30.0%
• Melting Point: The SDD is amorphous and is characterized by glass transition temperature (Tg) rather than melting point; amorphous character and absence of residual crystallinity must be confirmed by DSC/XRPD; no official melting point for orforglipron free acid or the calcium salt has been found in publicly available CHP/USP/EP, FDA, or EMA materials, and the 268–275 °C stated on some suppliers’ COAs is single-source data and not a release specification
• Chemical Name: 3-[(1S,2S)-1-[5-[(4S)-2,2-Dimethyltetrahydro-2H-pyran-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl]-1H-indol-1-yl]-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one
• Chiral Centers: (1S,2S) cyclopropane and two (4S) positions—four defined stereocenters in total
• API Solubility: Freely soluble in DMSO (about 100–125 mg/mL, sonication required), DMF, and dichloromethane; soluble in methanol; insoluble in water and ethanol
• Solid-State Characterization: XRPD should show an amorphous halo with no crystalline diffraction peaks of the API; DSC should show a single glass transition; joint confirmation by SEM, DSC, and XRPD is recommended
• Storage: Seal tightly, protect from light and moisture; refrigerated storage at 2–8 °C recommended; the amorphous form is sensitive to temperature and humidity, and recrystallization risk must be controlled in a dry environment

Applications

• Long-term weight management (obesity/overweight): On April 1, 2026, the US FDA approved Foundayo (orforglipron) tablets, as an adjunct to a reduced-calorie diet and increased physical activity, for weight reduction and long-term maintenance in adults with obesity or overweight adults with at least one weight-related comorbidity; starting dose 0.8 mg once daily, escalating to 2.5 mg after at least 30 days and to 5.5 mg after a further 30 days, with further increases to 9 mg, 14.5 mg, and 17.2 mg based on efficacy and tolerability; dosing is not restricted by food or water intake
• Type 2 diabetes mellitus (T2DM): The pivotal Phase III ACHIEVE and ATTAIN programs demonstrated dose-dependent HbA1c reduction and weight loss in T2DM and obesity populations; regulatory review for this indication is still ongoing (an EMA committee has issued positive opinions for obesity and type 2 diabetes, and a marketing application has been submitted in China); refer to the latest official announcements for formal approval status
• Solubility-enhancement technology development for poorly soluble drugs: As an amorphous solid dispersion intermediate for a BCS Class II molecule (low solubility, high permeability), used for ASD carrier screening, drug loading and drug-polymer ratio optimization, supersaturation and recrystallization inhibition studies, and in vitro-in vivo correlation (IVIVC) evaluation of dissolution and exposure
• Formulation and manufacturing: Suitable for formulation development of oral solid dosage forms such as tablets and capsules, content uniformity and blend homogeneity optimization, analytical method development and validation, stability studies, and GMP scale-up and CMO/CDMO contract manufacturing from clinical stages through commercialization

Safety Notice: This product is a pharmaceutical intermediate/formulation intermediate intended solely for compliant research and pharmaceutical manufacturing use; it is not intended for end clinical use or self-medication guidance. The marketed formulation label carries a boxed warning for thyroid C-cell tumors; it is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2).

Product information: please contact us. This information is for reference only.