Orforglipron Hemicalcium Hydrate

Physical and Quality Control Parameters

Appearance: White to off-white crystalline powder, odorless; the crystal form is the stable Form II, with high crystallinity and good flowability, suitable for direct compression.

Solubility: Easily soluble in water (solubility approximately 50 mg/mL, 25℃), soluble in methanol and ethanol, slightly soluble in ethyl acetate; its water solubility is approximately 60 times higher than that of the free base (0.8 mg/mL), meeting the requirements for rapid dissolution in formulations.

Stability:

Stable when stored in a sealed container, protected from light, at 2-8℃, with a shelf life of 36 months; the crystal water and calcium ions synergistically stabilize the molecular structure, showing no significant degradation under light and high temperatures (≤60℃), superior to the free base and other salt forms.

In solution, it is stable at pH 3.0-7.5; under strong acidic conditions, the pyran ring may open, and under strong alkaline conditions, the oxadiazolone ring may hydrolyze. It is recommended to control the pH of the formulation between 5.0 and 6.5. Key Quality Control Indicators (API Level)

Chemical Purity: ≥99.8% (HPLC area normalization method, detection wavelength 254 nm)

Chiral Purity: ≥99.9% ee (Chiral SFC, Chiralpak IA column)

Calcium Content: 2.80%-3.00% (EDTA titration method)

Moisture Content: 1.60%-1.80% (Karl Fischer method, corresponding to 1 molecule of crystal water)

Crystalline Form Purity: Form II ≥99.5% (XRPD detection)

Residual Solvents: Complies with ICH Q3C limits (ethanol ≤0.5%, ethyl acetate ≤0.5%)

Heavy Metals: ≤1 ppm (ICP-MS)

Related Substances: Single impurity ≤0.05%, total impurities ≤0.2%

III. Synthesis Route and Key Process

Olanzapine hemicalcium salt hydrate is prepared from olanzapine free base through salt formation, crystallization, and drying. The core steps are as follows:

Salt Formation Reaction

Dissolve the free base (purity ≥99.8%, chiral purity ≥99.9% ee) in anhydrous ethanol, heat to 40-45℃ and stir to dissolve, controlling the concentration to 0.1 g/mL.

Slowly add 0.5 eq of anhydrous calcium chloride ethanol solution (concentration 0.1 mol/L), stir for 1 hour to form a white turbid solution; calcium ions coordinate with the carbonyl oxygen of the free base, promoting salt formation.

Crystallization and Purification

Cool the reaction solution to 20-25℃, stir for 2 hours to complete crystallization, and filter to collect the solid.

Wash the crystals 2-3 times with cold anhydrous ethanol to remove residual calcium chloride and free base.

Dry in a vacuum drying oven at 40℃ for 12 hours, controlling the moisture content to 1.60%-1.80%, to obtain the hemicalcium salt hydrate with a yield of approximately 92%. Crystalline form control: The heating rate (1℃/min) must be controlled during the drying process to prevent the loss of crystal water; if the crystalline form is impure, recrystallization can be performed using an ethanol-water system (volume ratio 9:1) to convert it into the stable Form II.