Field of the Invention
The present invention relates to a process for preparing parenteral composition of Ondansetron hydrochloride. The composition is useful for the treatment of nausea and vomiting associated with cancer chemotherapy and that occurring postoperatively.
Background of the Invention
Oral administration in the form of a conventional tablet, pill or capsule constitutes the preferred route of administration of Pharmaceuticals since this route is generally convenient and acceptable to patients. However, one of the major concerns associated with oral administration, is patient compliance. This is particularly evident in the case of pediatric or geriatric patients who are unwilling or face difficulty in swallowing such conventional dosage forms. Further, it is highly desirable, particularly in the treatment of acute conditions, that pharmaceutical compositions have a rapid and consistent onset of action combined with suitable bioavailability.
Parenteral administration, apart from providing quicker onset of action, results in more predictable blood serum concentrations of the drug. Further, losses in the gastrointestinal tract due to metabolism, binding to food and other causes are eliminated. For similar reasons, parenteral administration permits dose reduction. It is also the preferred method of drug delivery in emergency situations and is useful in non-cooperative patients.
Ondansetron, chemically described as, 1,2,3,9-tetrahydro-9-methyl-3- [(2-methyl-IH-imidazol-l-yl) methyl] -4H-carbazol-4-one, is an antiemetic agent due to its selective action on the 5-HT3 receptors.
Ondansetron is available commercially as tablets, orally disintegrating tablets, solutions and parenterals. In marketed compositions (sold under brand name ZOFRAN® by Glaxo), ondansetron is used as a free base in rapidly disintegrating tablets and as a hydrochloride salt in injections, tablets for oral administration and oral solutions. Currently available parenteral dosage form of ondansetron is Zofran and Zofran Preservative Free.
U.S. Patent 4,695,578 discloses ondansetron and physiologically acceptable salt or solvate thereof.
Chinese Patent Application No. 1555795 discloses ondansetron hydrochloride injection in the form of freeze dried powder prepared from ondansetron hydrochloride, pharmacologically acceptable excipient and water for injection. The process involves dissolving ondansetron

hydrochloride in the water, adding excipient, stirring, regulating pH value, filtering, and freeze drying.
PCT Application WO9800159 discloses compositions for administering acid addition salts of compounds, including ondansetron hydrochloride, by intramuscular injection. In the method disclosed, a sterile parenteral composition of a liquid vehicle containing the acid addition salt in solution is adjusted in pH for reducing the development of undesirable side effects of the material or provided at a pH within a range of about 5.5 to 7.0.
The process of developing parenteral composition of Ondansetron hydrochloride is a challenging job for the formulator because the drug has pH dependent solubility. Solubility of Ondansetron Hydrochloride decreases with increasing pH. As a consequence, pH of the solution plays a major role in the stability of ondansetron hydrochloride solution with precipitation occurring in solution with a pH of 5.7 and more.
It was observed that the sequence of addition of the pharmaceutically acceptable excipients was critical for obtaining the parenteral compositions of ondansetron hydrochloride, having desired characteristics. Any change in the sequence of addition leads to undesirable characteristics such as precipitation of the drug, turbidity/ haziness, non solubilization of the drug and/ or pH not in the pharmacopoeial limits.
Surprisingly, it was observed that addition of excipients in a particular sequence gives a clear composition having desired pH. The principle being that ondansetron hydrochloride requires a sufficiently acidic environment to be maintained in clear solution. Therefore a hydroxy acid is added to the solvent before the addition of ondansetron hydrochloride in order to obtain a clear solution, followed by the addition of base. This process leads to a buffered system, and gives a clear solution with the desired pH. Further, this process reduces the need to use extra excipients in the composition, thereby decreasing the processing time and the cost of product.
Summary Of The Invention
According to one embodiment there is provided a process for preparing a parenteral composition of ondansetron hydrochloride, the process comprising the steps of: a) adding ondansetron hydrochloride into an aqueous solvent comprising one or more hydroxy acids to obtain a clear solution; b) adding one or more bases and optionally one or more pharmaceutically acceptable excipients to the solution of step (a) to obtain the parenteral composition.

According to another embodiment there is provided a process for preparing a parenteral composition of ondansetron hydrochloride, the process comprising the steps of: a) adding ondansetron hydrochloride into an aqueous solvent comprising citric acid to obtain a clear solution; b) adding sodium citrate and optionally one or more pharmaceutically acceptable excipients to the solution of step (a) to obtain the parenteral composition.
Detailed Description of the Invention
The process for preparing the parenteral composition of ondansetron hydrochloride comprises the steps of: a) adding ondansetron hydrochloride into an aqueous solvent comprising one or more hydroxy acids to obtain a clear solution; b) adding one or more bases and optionally one or more pharmaceutically acceptable excipients to the solution of step (a) to obtain the parenteral composition.
The parenteral composition of ondansetron hydrochloride may be used in the form of an intravenous injection, intramuscular injection or subcutaneous injection. The injection may be filled in ampoules, vials, and plastic bags and may be premixed with diluents suitable for injection.
Ondansetron hydrochloride used in the composition is preferably Ondansetron hydrochloride dihydrate.
The term "clear solution" is referred to a solution, which is free from any haziness, turbidity, unsolubilized ondansetron hydrochloride or any other particles as observed upon visual inspection.
The pH of the intravenous injection of ondansetron hydrochloride may range from 3.3 - 4.0. The pH of the premixed intravenous injection of Ondansetron Hydrochloride may range from 3.0-4.0.
The parenteral composition of ondansetron hydrochloride includes an acidic buffer. The acidic component of the buffer is preferably a hydroxy acid. The hydroxy acids may be selected from one or more of malic acid, lactic acid, tartaric acid or citric acid. Preferred hydroxy acid is citric acid.
The base component (conjugate base) of the buffer may be a soluble salt, preferably an alkali metal salt, of the hydroxy acid. The "base" may be selected from one or more of an alkali metal salt of maleate, lactate, tartrate and citrate. Preferred base is sodium citrate.

The "pharmaceutically acceptable excipients" may be selected from one or more of preservatives and tonicity contributors.
Suitable preservatives may be selected from one or more of phenylmercuric nitrate, thimersal, benzalkonium chloride, benzethonium chloride, phenol, cresol, chlorobutanol and parabens (methyl paraben & propyl paraben).
Suitable tonicity contributors may be selected from one or more of sodium chloride, potassium chloride, dextrose, mannitol, sorbitol and lactose.
The aqueous solvent may be water for injection or any other aqueous medium suitable for parenteral delivery.
In all cases, the parenteral composition must be sterile and stable. Techniques such as asceptic filtration, autoclaving, steaming and irradiation may be used for sterilization.
The following non-limiting examples illustrate the process for preparing a parenteral composition of ondansetron disclosed in various embodiments of the specification.
Example 1 :
Intravenous Injection
(Table Remove)

pH of the clear solution is 3.72.
Brief Manufacturing process:
1. Citric acid was dissolved in water to obtain a solution.
2. Ondansetron hydrochloride was added to the solution obtained in step 1 to obtain a
clear solution

3. To the clear solution of step 2 sodium citrate followed by sodium chloride was added to
obtain a solution.
4. The volume of solution obtained in step 3 was made up with water to obtain a
parenteral composition.
5. The parenteral composition of step 4 was filtered through 0.22um membrane filter and
filtered in 2ml glass vials and sealed with rubber stopper and aluminium seal.
Comparative Example 1 : Intravenous Injection
The composition is same as that of Example 1.
Brief Manufacturing process
1. Ondansetron hydrochloride was dissolved in water to obtain a solution.
2. To the solution of step 1, sodium citrate was added, a hazy solution was obtained.
3. To the hazy solution obtained in step 2, citric acid, followed by sodium chloride was
added to obtain a clear solution.
4. The volume of clear solution obtained in step 3 was made up with water.
5. The clear solution of step 4 was filtered through 0.22um membrane filter and filtered in
2ml glass vials and sealed with rubber stopper and aluminium seal.
Comparative Example 2: Intravenous Injection
The composition is same as that of Example 1.
Brief Manufacturing process
1. Sodium chloride was added to water to obtain a solution.
2. To the solution obtained in step 1 citric acid , followed by sodium citrate was added to
obtain a clear solution.
3. To the clear solution obtained in step 2 ondansetron hydrochloride was added,
(precipitated solution was obtained).
Comparative Example 3: Intravenous Injection
The composition is same as that of Example 1.

Brief Manufacturing process:
1. Water was heated to 80-85°C and to this methyl paraben and propylparaben were
dissolved and then cooled to obtain a solution.
2. To the solution obtained in step 1, citric acid was dissolved, followed by addition of
ondansetron hydrochloride to obtain a clear solution.
3. To the clear solution obtained in step 2, sodium citrate, followed by sodium chloride was
added to obtain a solution.
4. The volume of solution obtained in step 3 was made up with water to obtain a solution.
5. The solution of step 4 was filtered through 0.22um membrane filter and filtered in 20ml
glass vials, purged with nitrogen and sealed with rubber stopper and aluminium seal.
Example 3
Intravenous Injection (with preservative)
The composition is same as that of Example 2,
Brief Manufacturing process
1. Water was heated to 80-85°C and to this methyl paraben and propylparaben were
dissolved and then cooled to obtain a solution.
2. Separately, Citric acid was dissolved in water, followed by addition of Ondansetron
hydrochloride and sodium citrate to obtain a clear solution.
3. The clear solution obtained in step 2 was added to solution obtained in step 1 to obtain
a homogenous solution.
4. To the homogenous solution of step 3 sodium chloride was added to obtain a solution.
5. The volume of solution obtained in step 4 was made up with water to obtain a solution.
6. The solution of step 5 was filtered through 0.22um membrane filter and filtered in 20ml
glass vials, purged with nitrogen and sealed with rubber stopper and aluminium seal.

Brief Manufacturing process
1. Sodium chloride was added to water to obtain a solution.
2. To the solution obtained in step 1 citric acid was added , followed by ondansetron
hydrochloride (precipitated solution was obtained).
3. To the precipitated solution obtained in step 3, sodium citrate was added,
(Ondansetron hydrochloride remains unsolubilized).
Visual Inspection Of the Parenteral compositions of Example 1 & Comparative examples 1-3 (Table Remove)

* The haziness obtained after step 2 may be of concern during scale up.
Example 2:
Intravenous Injection (with preservative) (Table Remove)

Example 4: inlection Premixed • 32mg/50ml bag

(Table Remove)
pH: 3.0-4.0
Brief Manufacturing process:
1. Citric acid was dissolved in water to obtain a solution.
2. Ondansetron hydrochloride was added to the solution obtained in step 1 to obtain a
clear solution
3. To the clear solution of step 2 sodium citrate followed by dextrose was added to obtain
a solution.
4. The volume of solution obtained in step 3 was made up with water.
5. The solution of step 4 was filtered through 0.22um membrane filter and filtered, filled in
bags, purged with nitrogen and sealed.

1. A process for preparing a parenteral composition of ondansetron hydrochloride, the
process comprising the steps of: a) adding ondansetron hydrochloride into an aqueous
solvent comprising one or more hydroxy acids, to obtain a clear solution; b) adding one
or more bases and optionally one or more pharmaceutically acceptable excipients to the
solution of step (a) to obtain the parenteral composition.
2. The process according to Claim 1, wherein the hydroxy acids may be selected from one
or more of malic acid, lactic acid, tartaric acid and citric acid.
3. The process according to Claim 1, wherein the base may be selected from one or
more of an alkali metal salt of maleate, lactate, tartrate and citrate.
4. The process according to Claim 1, wherein the pharmaceutically acceptable excipients
may be selected from one or more of preservatives and tonicity contributors.
5. The process according to Claim 4, wherein the preservatives may be selected from one
or more of phenylmercuric nitrate, thimersal, benzalkonium chloride, benzethonium
chloride, phenol, cresol, chlorobutanol and parabens.
6. The process according to Claim 4, wherein the tonicity contributors may be selected
from one or more of sodium chloride, potassium chloride, dextrose, mannitol, sorbitol
and lactose.
7. The process according to claim 1, wherein the hydroxy acid is citric acid and the base is
sodium citrate.
8. A process for preparing a parenteral composition of ondansetron hydrochloride
substantially described and exemplified herein.