Solid-state characterisation of the new crystal form of resmetirom pharma grade API is a release precondition for oral tablets, capsules, granules, and injectable presentations. Differential scanning calorimetry under USP <891> and powder X-ray diffraction under USP <941> establish polymorph identity, while residual solvent measurement by headspace gas chromatography under USP <467> applies an ICH Class 3 total limit of 5000 ppm. Particle size distribution is measured by laser diffraction under USP <429>; the D10, D50 and D90 values determine whether direct compression can meet content uniformity under USP <905>. The API is manufactured under ICH Q7 and the approved oral tablet strengths are 60 mg, 80 mg, and 100 mg. Published data for this specific new crystal form are limited, so the following downstream applications are constructed around process-specific control ranges that must be verified against the assigned pharmacopoeial monograph. When the new crystal form is used in solid oral dosage forms, comparative dissolution testing under USP <711> is required because polymorph changes can alter release rate without changing assay or total impurities.

Direct Compression of the 60 mg and 80 mg Tablet Strengths

Direct compression of the 60 mg and 80 mg strengths is selected when the new crystal form has acceptable flow per USP <1174> and compactability under USP <1217>. A feasibility batch for the 60 mg strength uses a 200 mg core with API load of 30.0% w/w; the 80 mg strength uses a 250 mg core with API load of 32.0% w/w. The filler system is microcrystalline cellulose PH-102 and anhydrous lactose in a 1:1 ratio; croscarmellose sodium is included at 5.0% w/w, colloidal silicon dioxide at 0.5% w/w, and magnesium stearate at 0.75% w/w. When ambient relative humidity exceeds 60%, the filler blend is pre-dried at 50°C until loss on drying is below 2.0% under USP <731>. The API is pre-screened through a 600 µm sieve, blended in a bin blender at 25 rpm for 15 min, and lubricated for 3 min. Prolonged lubrication beyond 5 min is deliberately avoided because magnesium stearate forms a hydrophobic film on the crystal surface, producing a measurable drop in breaking force and dissolution. The blend is compressed on a rotary tablet press with 10 mm round concave tooling, pre-compression force 4 kN, and main compression force 12 kN to 15 kN. Tablet breaking force is held at 80 N to 120 N under USP <1217>; friability is below 1.0% under USP <1216>; disintegration time is less than 15 min under USP <701>. Dissolution is tested under USP <711>; a provisional acceptance criterion of Q = 80% at 30 min is applied only after the dissolution medium is justified by solubility data for the new crystal form. The tablets are film-coated with Opadry II at a 3.0% w/w weight gain in a perforated pan coater at an inlet temperature of 60°C, bed temperature 38°C to 42°C, pan speed 12 rpm, and spray rate 8 g/min to 15 g/min. The finished tablet is packed in HDPE bottles with desiccant and is controlled by 21 CFR 210, 21 CFR 211, ICH Q3D elemental impurities, and ICH Q1A(R2) stability.

Aqueous high-shear granulation is required when direct compression shows segregation at the 100 mg dose or when the powder angle of repose exceeds 40° under USP <1174>. The dry premix contains the API at 28.6% w/w of the final blend, with lactose monohydrate and microcrystalline cellulose in a 1:1 ratio, crospovidone at 4.0% w/w, and povidone K30 binder solution at 5.0% w/w solids. Water is added at 25% to 35% w/w of the dry powder mass in a top-driven high-shear granulator; the endpoint is determined by torque rise rather than by added water volume alone. For a 25 kg batch, target power consumption is 6 kW to 8 kW; a torque plateau indicates granule densification, while a sudden torque decrease can signal overloading with water and wall incrustation. The wet mass is screened through a 4 mm mesh, dried in a fluid-bed dryer at 60°C inlet air until loss on drying is below 2.0% under USP <731>, and milled through an 800 µm screen. Because aqueous granulation can induce polymorph conversion, dried granules are sampled for powder X-ray diffraction under USP <941>; if the diffractogram differs from the reference pattern outside the acceptance window, the batch is not compressed. Extragranular croscarmellose sodium at 1.0% w/w, colloidal silicon dioxide at 0.5% w/w, and magnesium stearate at 0.5% w/w are added before compression. The final tablet core for the 100 mg strength is 350 mg; content uniformity is tested under USP <905> with an acceptance value not exceeding 15.0. If the release moisture of the granule exceeds 1.5%, the primary packaging is limited to Aclar or cold-form foil blisters.

What Changes When the New Crystal Form Is Encapsulated Into Hard Capsules?

Encapsulation shifts the process control focus from tablet compactability to powder bed uniformity and shell compatibility. A representative 60 mg capsule uses a size 2 hard gelatin shell with a fill weight of 180 mg and API load of 33.3% w/w. The diluent is mannitol or pregelatinized starch; colloidal silicon dioxide is added at 1.0% w/w, and sodium stearyl fumarate at 1.0% w/w. Sodium stearyl fumarate is preferred over magnesium stearate when low shell brittleness and clean tamping pin operation are both required; fill weight is controlled on a dosator-type capsule filler with a powder bed height of 40 mm, 5 tamping stations, and a compression setting of 2.0 mm. Fill weight is checked every 30 min; if the relative standard deviation exceeds 3.0%, the dosing station height is adjusted. The filled capsules are dedusted and equilibrated at 25°C/40% RH until shell moisture reaches 12% to 14%. Shell moisture below this range causes cap-body cracking on high-speed closing, and moisture above this range can soften the shell and delay disintegration under USP <701>. Dissolution is run under USP <711> and content uniformity under USP <905>; microbial limits are controlled under USP <61> and USP <62>. The finished capsule is packaged in PVC/PE/PVDC blisters if open-dish stability under ICH Q1A(R2) at 40°C/75% RH demonstrates moisture sensitivity; hypromellose shells are substituted when the fill must remain below 1.0% residual moisture.

Fluid-bed layering on microcrystalline cellulose spheres produces oral granules for unit-dose sachets. The API is suspended in an aqueous binder solution of povidone K30 at 5.0% w/w solids and sprayed onto 300 µm to 425 µm microcrystalline cellulose spheres in a Wurster column. The layering load is controlled at 12% to 18% w/w API; higher layering loads may produce friable granule surfaces and variable fill weight. Inlet temperature is held at 55°C, product temperature at 35°C to 38°C, atomizing air pressure at 1.5 bar, and spray rate at 5 g/min to 8 g/min for a 1 kg laboratory batch. The layered granules are overcoated with low-viscosity hypromellose at a 2.0% w/w weight gain to reduce fines. Granule size is controlled to a D50 of 350 µm to 500 µm by laser diffraction under USP <429>; the fraction below 150 µm is kept below 10% because excess fines cause dose dumping on reconstitution. The final sachet is filled to 1.0 g for a 60 mg dose; uniformity of mass is tested per Ph. Eur. 2.9.5. The reconstitution target is dispersion in water within 30 s; this is verified by an in-house dispersion method because no harmonized pharmacopoeial monograph covers taste-masked granules. Moisture is controlled below 2.0% by loss on drying, and the finished sachet is packed in trilaminate aluminium foil.

If the API Is Buffered in an Injectable Co-Solvent System

Parenteral solution development for the new crystal form begins with pH-solubility profiling in compendial buffers and cannot be inferred from oral dissolution. A representative injectable solution at 10 mg/mL uses 25% v/v PEG 300, 10% v/v ethanol, and 65% v/v phosphate buffer at pH 7.0. The API is dissolved first in the ethanol and PEG 300 mixture, then diluted with buffer. If visible precipitation occurs after 24 h at 2°C to 8°C, the API concentration is reduced or the co-solvent ratio is increased. Osmolality is adjusted to 280 mOsm/kg to 320 mOsm/kg under USP <785>; the solution is filtered through a 0.22 µm PVDF membrane and the filter is validated according to PDA Technical Report 26. The sterile-filtered solution is filled into 5 mL Type I glass vials under an isolator. Particulate matter is controlled under USP <788> with not more than 6000 particles per container at ≥10 µm and not more than 600 particles per container at ≥25 µm. Bacterial endotoxin is controlled under USP <85>, sterility under USP <71>, and container closure integrity under USP <1207>. The final pH is held between 6.0 and 8.0 because the injection route is sensitive to both acidic and alkaline hydrolysis; the finished solution is stored at 2°C to 8°C unless room-temperature stability is confirmed under ICH Q1A(R2). The impurity profile must match the oral monograph under ICH Q3B before oral-injectable bridging is accepted.

Lyophilised Injectable Cake Engineering and Residual Moisture Thresholds

Lyophilisation is selected when the injectable solution has insufficient hydrolytic stability or when the new crystal form requires a solid-state injectable presentation. A 20 mg vial is filled at 2 mL with a solution containing 10 mg/mL API, 5.0% w/v mannitol, 2.0% w/v trehalose dihydrate, and 10 mM phosphate buffer at pH 7.2. The solution is filled into 5 mL Type I glass vials and partially stoppered. The lyophilisation cycle is developed by freeze-drying microscopy; a representative cycle freezes the product at -45°C for 120 min, conducts primary drying at -25°C shelf temperature with a chamber pressure of 100 mTorr for 36 h, and then ramps to 40°C for secondary drying of 8 h. If the new crystal form is converted to an amorphous state during lyophilisation, residual moisture measured by Karl Fischer under USP <921> must be below 2.0%; if the cake remains crystalline, a higher residual moisture limit is justifiable only with supporting stability data. Cake collapse is the principal process failure and occurs when the primary drying shelf temperature exceeds the collapse temperature by more than 2°C, yielding a shrunken or cracked cake with unacceptable reconstitution time. The finished vial is reconstituted with 2 mL sterile water for injection; reconstitution time should not exceed 60 s for a 20 mg dose. After reconstitution, particulate matter is controlled under USP <788>, sterility under USP <71>, endotoxin under USP <85>, and container closure integrity under USP <1207>. Processing is governed by EU GMP Annex 1 aseptic requirements and stability by ICH Q1A(R2).