PROCESS FOR MAKING AMLODIPINE, DERIVATIVES THEREOF, AND PRECURSORS THEREFOR

1 . A process, which comprises the steps of:

(a) assaying a sample from a batch of phthalimidoamlodipine for at least one phthalimidoamlodipine impurity selected from the group consisting of compounds 2b-2f:

(b) determining whether said at least one phthalimidoamlodipine impurity is contained in said sample below a predetermined limit, and, if below said predetermined limit;

(c) subjecting said phthalimidoamlodipine batch to deprotection to form a batch of amlodipine.

2 . The process according to claim 1 , which further comprises crystallizing said batch of phthalimidoamlodipine prior to said assaying step.

3 . The process according to claim 2 , which further comprises converting said batch of amlodipine to a pharmaceutically acceptable salt of amlodipine; and combining said pharmaceutically acceptable salt of amlodipine with at least one pharmaceutically acceptable excipient to form pharmaceutical unit dosage forms containing an effective amount of said amlodipine salt.

4 . The process according to claim 3 , which further comprises assaying a sample of at least one of said batch amlodipine, said amlodipine salt, or said pharmaceutical unit dosage form, for an amlodipine impurity selected from the group consisting of (1b)-(1f):

5 . The process according to claim 1 , wherein said phthalimidoamlodipine impurity is 2b or 2c.

6 . A process for making a pharmaceutical active ingredient, which comprises:

forming in an alcohol solvent a batch of phthalimidoamlodipine;

deprotecting said phthalimidoamlodipine to form a batch of amlodipine;

converting said batch of amlodipine to a salt thereof;

assaying a sample from said batch of amlodipine or its salt to determine the amount of at least one of compounds (1b)-(1f):

and if said determined amount of said at least one compound of formula (1b)-(1f) is below 0.5 wt %, then releasing said amlodipine batch or salt thereof.

7 . The process according to claim 6 , wherein said assaying determines the amount of compound of formula (1b), (1c) or both.

8 . The process according to claim 7 , wherein the amount of said compound of formula (1b), (1c), or both are each less than 0.2 wt % before said batch of amlodipine or its salt is released.

9 . The process according to claim 6 , wherein said alcohol solvent is ethanol or isopropanol.

10 . A process which comprises:

subjecting at least one of the following compounds (1b)-(1f):

in sufficiently pure state to HPLC analysis under a set of conditions to obtain a reference standard analytical result;

subjecting a sample from a batch of amlodipine or a salt thereof to HPLC analysis under said set of conditions to obtain a sample analytical result;

determining the amount of said compound in said sample of amlodipine or salt thereof by comparing said reference standard analytical result to said sample analytical result; and

releasing said batch of amlodipine or its salt if said amount of said compound is 0.2 wt. % or less.

11 . The process according to claim 10 , wherein said compound is a compound of formula (1b) or (1c).

12 . The process according to claim 10 , wherein said comparison is performed by an automated process.

13 . The process according to claim 10 , wherein said determination of the amount of said compound involves the Response factor for said compound obtained as said reference standard analytical result.