Tm tubular maximum for reabsorption TZD thiazolidinedione ULN upper limit of normal ULOQ upper limit of quantification UGT uridine diphosphate glucuronosyltransferase II. Quality findings Drug substance (active ingredient) Dapagliflozin is a synthetic aryl glycoside. It has multiple chiral centres but the drug is a single enantiomer. Epimerisation is unlikely. Figure 1. Chemical structure of dapagliflozin dapagliflozin (propylene glycol, monohydrate solvate) The structure is not closely related to that of other antidiabetic drugs; it perhaps bears some similarity to miglitol (Figure 2). Figure 2. Chemical structure of miglitol. The drug substance used in tablet manufacture is the 1,2-propanediol, monohydrate solvate of dapagliflozin (1,2-propanediol is also known as propylene glycol). The drug substance is crystalline. Dapagliflozin aqueous solubility is relatively high and independent of pH. Drug product The proposed 5 mg and 10 mg (as dapagliflozin) tablets are, immediate release, film coated tablets with conventional formulations. Both strengths are yellow; they are distinguished by size, shape (5 mg round; 10 mg diamond) and tablet markings (‘5’ and vs and Neither is scored. ‘1427’; ‘10’ ‘1428’). Some clinical trials also used 2.5 mg tablets. The Phase III clinical formulation differed from the proposed formulation but no impact on bioavailability is expected. The tablets are packed in aluminium/aluminium blisters in 7 or 28 tablet packs. Supportive dissolution and disintegration data are available from the proposed manufacturing sites. The proposal was considered acceptable. Levels of impurities in dapagliflozin tablet batches are low although the proposed limits are lax. Limited on-going related substance testing will be done via an annual program testing stability of a batch. The approach was considered acceptable. Tablet stability data otherwise support the proposed shelf life of 24 months when stored below 30C.
Tm tubular maximum for reabsorption TZD thiazolidinedione ULN upper limit of normal ULOQ upper limit of quantification UGT uridine diphosphate glucuronosyltransferase II. Quality findings Drug substance (active ingredient) Dapagliflozin is a synthetic aryl glycoside. It has multiple chiral centres but the drug is a single enantiomer. Epimerisation is unlikely. Figure 1. Chemical structure of dapagliflozin dapagliflozin (propylene glycol, monohydrate solvate) The structure is not closely related to that of other antidiabetic drugs; it perhaps bears some similarity to miglitol (Figure 2). Figure 2. Chemical structure of miglitol. The drug substance used in tablet manufacture is the 1,2-propanediol, monohydrate solvate of dapagliflozin (1,2-propanediol is also known as propylene glycol). The drug substance is crystalline. Dapagliflozin aqueous solubility is relatively high and independent of pH. Drug product The proposed 5 mg and 10 mg (as dapagliflozin) tablets are, immediate release, film coated tablets with conventional formulations. Both strengths are yellow; they are distinguished by size, shape (5 mg round; 10 mg diamond) and tablet markings (‘5’ and ‘1427’; vs ‘10’ and ‘1428’). Neither is scored. Some clinical trials also used 2.5 mg tablets. The Phase III clinical formulation differed from the proposed formulation but no impact on bioavailability is expected. The tablets are packed in aluminium/aluminium blisters in 7 or 28 tablet packs. Supportive dissolution and disintegration data are available from the proposed manufacturing sites. The proposal was considered acceptable. Levels of impurities in dapagliflozin tablet batches are low although the proposed limits are lax. Limited on-going related substance testing will be done via an annual program testing stability of a batch. The approach was considered acceptable. Tablet stability data otherwise support the proposed shelf life of 24 months when stored below 30C.
auspar-dapagliflozin-propanediol-monohydrate-130114.docx