# US 10,870,654 B2 · Pharmaceutically acceptable salts and polymorphic forms of hydrocodone benzoic acid enol ester and processes for making same

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,870,654 B2
- Document ID: US10870654B2
- Status: Granted
- Kind: B2
- Application number: 16/356,938
- Filed: 2019-03-18
- Published: 2019-09-19
- Granted: 2020-12-22
- Earliest claimed: 2013-03-08
- Assignees: KemPharm, Inc.
- Applicants: KemPharm, Inc.
- Inventors: Travis Mickle; Sven Guenther; Christal Mickle; Guochen Chi; Jaroslaw Kanski; Andrea K. Martin; Bindu Bera
- Web page: https://patentgrep.com/patent/US10870654B2

## CPC

- C07D 489/04: Salts; Organic complexes
- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- C07D 489/02: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Compositions comprising hydrocodone benzoic acid enol ester to form novel prodrugs including hydrocodone benzoic acid enol ester salts, and various polymorphs. Also provided are processes for the preparation of hydrocodone benzoic acid enol ester salts, and various polymorphs.

## Claims

### Claim 1

A process for the preparation of the following compound:
wherein the compound is a polymorphic form of hydrocodone benzoic acid enol ester, wherein the polymorphic form is Form I and Form I has an x-ray powder diffraction pattern comprising peaks at about the following 2θ values: 9.05, 12.32, 13.16, 14.94, and 18.57 comprising the steps of:
(a) preparing a mixture comprising hydrocodone free base and either benzoic anhydride or benzoyl chloride and,
(b) heating the mixture to a temperature in the range of about 80° C. to about 160° C.

### Claim 2 (depends on 1)

The process of claim 1 further comprising the step of adding concentrated hydrochloric acid to the mixture to produce a compound having a following structure:

### Claim 3 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of the compound prepared according to the process of claim 1 and a pharmaceutically acceptable excipient.

### Claim 4 (depends on 2)

A pharmaceutical composition comprising a therapeutically effective amount of the compound prepared according to the process of claim 2 and a pharmaceutically acceptable excipient.

### Claim 5 (depends on 1)

The process of claim 1, wherein the mixture further comprises a suitable organic solvent.

### Claim 6 (depends on 5)

The process of claim 5, wherein the suitable organic solvent is selected from the group consisting of toluene, dimethylformamide, N-methyl-2-pyrrolidinone, and xylenes.

### Claim 7 (depends on 6)

The process of claim 6, wherein the toluene is substantially removed from the mixture via step (b).

### Claim 8 (depends on 1)

The process of claim 1, wherein the temperature of step (b) is in the range of about 126° C. to about 132° C.

### Claim 9 (depends on 1)

The process of claim 1, wherein the mixture further comprises a suitable base.

### Claim 10 (depends on 9)

The process of claim 9, wherein the suitable base is selected from the group consisting of pyridine, N,N-diisopropylethylamine (DIPEA), diazabicycloundecene (DBU), trimethylamine, and potassium benzoate.

### Claim 11 (depends on 1)

The process of claim 1, wherein Form I has an x-ray powder diffraction pattern further comprising peaks at about the following 2θ values: 6.16, 10.95, 11.91, 14.60, 17.04, 17.23, 17.80, 19.18, 20.66, 21.10, 22.15, 23.50, 26.07, and 28.39.