DESC:Field of Invention:
The present invention provides a novel mixture of solubilizing agent for the solubilization of poorly water soluble pharmaceutically active agents and preparation of pharmaceutical composition comprising the same.
Background of the invention:
Many pharmaceutical actives are poorly water soluble and therefore require relatively large volumes of solvent for dissolution. The usage of large volumes of solvents for solubilizing pharmaceutical actives is undesirable because the resulting solutions would be so dilute as to require impractically large dosages for delivering a therapeutically effective amount of active agents.
Multiple approaches to overcome these solubility problems have been disclosed. One approach has been to incorporate water, water-miscible co-solvents, and surfactants into the compositions.
US5554650 teaches the use of surfactant for the solubilization of poorly water soluble drugs. In a separate embodiment it also teaches the use of surfactant in combination with alcohol for the solubilization of poorly water soluble drugs.
W088/02625, discloses the solubilization of an ionized or partly-ionized pharmaceutical active in a mixture of water, polyethylene glycol, and polyvinylpyrrolidone;
US4794117 discloses the solubilization of hydrophobic pharmaceuticals in aqueous solutions of polyethylene glycol at controlled pH.
US4690823, discloses the solubilization of ibuprofen in a mixture of polyethylene glycol and a surfactant.
3
US3784684, discloses the solubilization of a pharmaceutical active in a mixture of polyethylene glycol and an alcohol having 2-8 carbons and 1-3 hydroxy groups
The present invention provides an alternative co-solvent mixture for the solubilization of poorly soluble active agent and preparation of pharmaceutical composition comprising the same.
Objective:
An Objective of the present invention is to provide a novel mixture of solubilizing agent for solubilizing poorly water soluble active agents.
Another objective of the present invention is to provide a pharmaceutical composition comprising a novel mixture of solubilizing agent for the solubilization of poorly water soluble active agents.
Another objective of the present invention is to provide a pharmaceutical composition comprising a poorly water soluble active agent and novel mixture of solubilizing agent.
Description
Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such compositions, components of the composition, referred to or indicated in this specification, individually or collectively and all combinations of any or more of such components or composition.
Definitions
For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the
4
light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have their meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as “consists of only”.
Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.
The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” are used interchangeably.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described. All publications mentioned herein are incorporated herein by reference.
The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products and processes are clearly within the scope of the disclosure, as described herein. The
5
term “pharmaceutical composition” refers to delivery system in which active agents are delivered to the patients. This could be in the form of tablet, capsule, injection, liquid etc. The term “pharmaceutically acceptable excipient” refers to inert substances other than active ingredients which are used in the preparation of pharmaceutical products. The term “parenteral” refers to drug delivery system in which the active agent(s) are directly administered into blood stream in form of injection surpassing first pass metabolism.
The term “excipients” as used herein means a component of a pharmaceutical product that is not an active ingredient. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic. The present invention relates to novel drug delivery system comprising Paracetamol and pharmaceutical acceptable salts thereof and process of manufacturing thereof.
In an embodiment the present invention provides a novel mixture of solubilizing agents for the solubilization of poorly soluble active agent. In another embodiment the present invention provides a stable parenteral formulation comprising a poorly soluble active agent wherein the active agent is solubilized by using a novel mixture of solubilizing agents, wherein the novel mixture of solubilizing agent comprises at least two or more solubilizing agents. The stable parenteral composition provides rapid onset of action, improved bioavailability and patient compliance for those who are unable to swallow tablet or patient who is suffering from nausea and vomiting.
In an embodiment the present invention provides a pharmaceutical composition comprising a poorly soluble pharmaceutically active agent, wherein the active agent is solubilized by a novel
6
mixture of solubilizing agents, wherein the novel mixture of solubilizing agent contains at least two or more solubilizing agents.
In an embodiment the present invention provides a pharmaceutical composition comprising a poorly soluble active agent and at least two or more solubilizing agents, wherein the pharmaceutical composition further comprises pharmaceutically acceptable excipients.
In an embodiment the present invention provides a pharmaceutical composition comprising a poorly water soluble active agent and novel mixture of solubilizing agents and a solvent vehicle, wherein the novel mixture of solubilizing agent comprises at least two or more solubilizing agents and wherein the solvent-vehicle is water.
In an embodiment the solubilizing agents are selected from alcohols, polymers, surfactants, N, N, Dimethyl acetamide.
In an embodiment the solubilizing agent are alcohols, wherein the alcohols are selected from monohydric or polyhydric alcohols. Examples of monohydric alcohols are benzyl alcohol, and the like; and as examples of polyhydric alcohols are propylene glycol, glycerin, polyethylene glycols.
In an embodiment the surfactant can be selected from ionic or non-ionic surfactants.
In an embodiment the solubilizing agents are a mixture of alcohol, surfactants and N-N dimethyl acetamide. In a preferred embodiment the solubilizing agents are a mixture of alcohol and N-N dimethyl acetamide, wherein the alcohols are preferably a mixture of two or more polyhydric alcohol, preferably the polyhydric alcohols are Polyethylene glycol, propylene glycol and a combination thereof.
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In an another embodiment, the present invention provides a stable parenteral formulation comprising a novel mixture of solubilizing agent and a poorly soluble pharmaceutically acceptable active agent, wherein the solubilizing agents are selected from alcohols and N-N dimethylacetamide. In a preferable embodiment the alcohols are a mixture of two or more polyhydric alcohol, wherein the polyhydric alcohols are Polyethylene glycol, propylene glycol and a combination thereof.
In an another embodiment, the present invention provides a stable parenteral formulation comprising a novel mixture of solubilizing agent and a poorly soluble pharmaceutically acceptable active agent, wherein the solubilizing agents are N-N dimethylacetamide, polyethylene glycol and propylene glycol and wherein the pharmaceutical composition comprises additional pharmaceutically acceptable excipients selected from preservative, stabilizer, pH regulator, buffering agents, solvents, chelating agents, antioxidants, surfactants, tonicity modifying agents, dispersing agents.
In a preferable embodiment the pharmaceutically acceptable excipient is pH regulator wherein the pH regulating agent may be one or more of maleic acid, hydrochloric acid, tartaric acid, sodium hydroxide, acetic acid, acetate, phosphoric acid, phosphate, citric acid, citrate, ethanolamine, triethanolamine, diethanolamine.
In an embodiment the solubilizing agents are present in the range of 2% to 40% vol/vol of the composition.
In an embodiment the pharmaceutically active agent is selected from Paracetamol, Diclofenac, Aceclofenac and the likes thereof.
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In an another embodiment parenteral formulation are suitable in form of intravenous, intramuscular, subcutaneous, intradermal, intra-arterial administration.
In an embodiment the parenteral formulation can be present in form of aqueous or non-aqueous solution, emulsion, suspension, dry powder or lyophilized powder.
In an embodiment, the present invention is directed to pharmaceutical composition for parenteral administration of active agent or a pharmaceutically acceptable salt thereof in the range of 6% to 60% wt/vol of the composition.
In an another embodiment the aqueous solution formulation suitable for parenteral administration comprises the active agent in the amount ranging from 10% to 60% wt/vol of the composition.
In an another embodiment the active agent is present in an amount ranging from 20 to 30% wt/vol of the composition.
In an another embodiment the aqueous solution further comprises antioxidant which prevent oxidation of the active agent in an aqueous solution from light, including ultraviolet, visible and/or fluorescent light, and/or exposure to free radicals generated from other sources, such as peroxides, superoxide anions, or metal ions.
In a preferred embodiment antioxidants of the invention are selected from the group consisting of vanillic acid, gallic acid, methyl paraben, m-cresol, phenol, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, monothioglycerol, ascorbic acid, sodium metabisulphite, sodium ascorbate, erythorbic acid, propionic acid or combinations thereof.
In an embodiment the preferred antioxidant is sodium metabisulphite present in an amount ranging from 0.05 to 0.5 more preferably 0.2% w/v.
9
In an embodiment the present invention provides combination of solubilizing agent comprising mixtures of polyethylene glycol, propylene glycol and N, N Dimethyl Acetamide.
In an another embodiment polyethylene glycol is present in an amount ranging from 5 to 20% w/v more preferably 10% w/v.
In an another embodiment propylene glycol is present in an amount ranging from 5 to 20% w/v more preferably 10% w/v.
In an another embodiment N,N Dimethyl acetamide is present in an amount ranging from 15 to 30% v/v more preferably 28% v/v.
In an another embodiment the present invention further comprises Benzyl alcohol in an amount ranging from 2 to 10% v/v.
In an embodiment the present invention provides a parenteral composition in form of aqueous solution comprising
a. About 20%-30% w/v of active agent, wherein the active agents can be selected from paracetamonl, diclofenac, aceclofenac or any other active agent having poor aqueous solubility and;
b. About 10% w/v Polyethylene glycol and;
c. About 10-11 % w/v propylene glycol and;
d. About 25-35 % w/v N-N Dimethyl acetamide and
e. About 0.2 % w/v sodium metabisulphite
In an embodiment the present invention provides a parenteral composition in form of aqueous solution comprising:
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a. About 25.00 % w/v of active agent, wherein the active agents can be selected from paracetamol, diclofenac, aceclofenac or any other active agent having poor aqueous solubility and;
f. About 10.00 % w/v Polyethylene glycol and;
g. About 10.00 % w/v propylene glycol and;
h. About 28.00 % w/v N-N Dimethyl acetamide and
i. About 0.200% w/v sodium metabisulphite
In an embodiment the present invention provides a parenteral composition in form of aqueous solution comprising:
a. About 25.00 % w/v of paracetamol
b. About 10.00 % w/v Polyethylene glycol and;
c. About 10.00 % w/v propylene glycol and;
d. About 28.00 % w/v N-N Dimethyl acetamide and
e. About 0.200% w/v sodium metabisulphite
In an embodiment the Polyethylene glycol, Propylene glycol and N-N Dimethyl Acetamide are present in 1:1:2.8 respectively.
In an another embodiment the present invention provides a parenteral composition in form of aqueous solution comprising:
a. About 20.00% w/v of active agent, wherein the active agents can be selected from paracetamol, diclofenac, aceclofenac or any other active agent having poor aqueous solubility and;
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b. About 10.00 % w/v Polyethylene glycol and;
c. About 10.00 % w/v propylene glycol and;
d. About 25% w/v N-N Dimethyl acetamide and;
e. About 0.200% w/v sodium metabisulphite
Wherein Polyethylene glycol, Propylene glycol and N-N Dimethyl Acetamide are present in 1:1:2.5 respectively.
In an another embodiment the present invention provides a parenteral composition in form of aqueous solution comprising:
a. About 30.00% w/v of active agent, wherein the active agents can be selected from paracetamol, diclofenac, aceclofenac or any other active agent having poor aqueous solubility and;
b. About 10.5 % w/v Polyethylene glycol and;
c. About 11.00 % w/v Polyethylene glycol and;
d. About 35% w/v N-N Dimethyl acetamide and;
e. About 0.200% w/v sodium metabisulphite
Wherein Polyethylene glycol, Propylene glycol and N-N Dimethyl Acetamide are present in 1:1:3.5 respectively.
In an embodiment the present invention provides a process for preparing a stable aqueous parenteral solution of the present invention. The process includes following steps:
i. Purge the water for injections with the help of nitrogen gas and;
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ii. Add and dissolve N-N Dimethylacetamide in step (i) with continuous stirring to get a clear solution and;
iii. Add and mix Paracetamol in solution obtain in step (ii) with continuous stirring to obtain a clear solution and;
iv. Add and mix benzyl alcohol in solution obtain in step (iii) with continuous stirring to obtain a clear solution and;
v. Add and dissolve propylene glycol in solution obtain in step iv under stirring to obtain a clear solution and;
vi. Add and dissolve polyethylene glycol in solution obtain on step v under stirring to obtain a clear solution and;
vii. Purge water for injection and cool down the temperature to 25°C- 30°C and add to above solution and;
viii. Add and mix Sodium metabisulphite under continuous stirring to above solution to obtain a clear solution and
ix. Adjust the pH between 4.5 to 6.5 adjust if required by hydrochloric acid & sodium hydroxide solution and make up the volume up to 500 liters by sterile water for injection.
In an embodiment the present invention provides parenteral formulation in form of aqueous solution comprising paracetamol and one or more excipients.
In an embodiment, the present invention provides a method of producing a pharmaceutical composition for parenteral administration.
The stable aqueous parenteral solution of the present invention may comprise pH adjusting agents in an amount sufficient to provide pH of the solution from about 3 to 8 more preferably
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between 4.50 to 6.50. The pH of the solution may be adjusted in the desired range by use of a pH adjusting agents and or a buffering agent known in the pharmaceutical art. The pH adjusting and/or buffering agent that may be used include, but are not limited to sodium hydroxide, hydrochloric acid, sulfuric acid, citric acid, acetic acid, tartaric acid, tromethamine, potassium hydroxide and the like and mixtures thereof wherein pH adjusting agent is sodium hydroxide.
In another embodiment of the invention, there is provided a parenteral solution comprising paracetamol does not contain any known impurities such as 4-aminophenol more than 0.1% as determined by HPLC after storage for more than 3 months, 6 months, 9 months and 12 months
In an another embodiment, the present invention provides a storage stable aqueous parenteral solution comprising paracetamol, wherein the solution retains at least 90% of the Paracetamol (% assay), as determined by HPLC, after storage for more than 3 months, for example, 6 months, 12 months, when stored at (i) 30°C ± 2° C, 75% RH ± 5% RH and at (ii) 25 ± 2 °C temperature and 60 ± 5 % RH.
In an another embodiment, the stable aqueous parenteral solution comprising Paracetamol is a clear solution (free of any crystals / precipitation) by visual inspection. The stable aqueous parenteral solution of the present invention when administered may have minimal or no pain at the site of injection.
In one embodiment, the stable aqueous parenteral solution of the present invention is supplied as a ready to administer solution. It does not require further dilution before administration.
In another embodiment, the stable aqueous parenteral solution of the present invention is supplied as a solution ready for dilution and it requires further dilution before administration. The diluted solution is for administration as intravenous infusion.
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In one embodiment, the stable aqueous parenteral solution of the present invention may be supplied in a suitable packaging material, for example, in a glass vial, in a glass ampoule, in a glass bottle, in a plastic bottle, in a PFS, in an auto-injector which contains a PFS or in a kit comprising a PFS and an auto-injector.
The following examples represent specific embodiments of the foregoing discovery, but are not representative of the entire scope of the invention.
Example-1 Formula for 250 mg/ml Paracetamol Injection:
Sr. No.
Ingredient
Per ml qty in percentage
1
Paracetamol
25.00%
2
Benzyl Alcohol
4.00%
3
Polyethylene glycol-400
10.0%
4
Propylene glycol
10.0%
5
N-N Dimethyl Acetamide
25.00%
6
Sodium Hydroxide (Pellets)
0.100%
7
Water for Injections
q.s.
Example-2 Formula for 250 mg/ml Paracetamol Injection
Sr. No.
Ingredient
Per ml qty in percentage
1
Paracetamol
25.00% w/v
2
Benzyl Alcohol
4.00% v/v
3
Polyethylene glycol-400
10.0% w/v
4
Propylene glycol
10.0% w/v
5
N-N Dimethyl Acetamide
28.00% v/v
6
Sodium metabisulphite
0.200% w/v
7
Sodium Hydroxide (Pellets)
0.100% w/v
15
8
Water for Injections
q.s.
i. Purge the water for injections with the help of nitrogen gas and;
ii. Add and dissolve N-N Dimethylacetamide in step (i) with continuous stirring to get a clear solution and;
iii. Add and mix Paracetamol in solution obtain in step (ii) with continuous stirring to obtain a clear solution and;
iv. Add and mix benzyl alcohol in solution obtain in step (iii) with continuous stirring to obtain a clear solution and;
v. Add and dissolve propylene glycol in solution obtain in step iv under stirring to obtain a clear solution and;
vi. Add and dissolve polyethylene glycol in solution obtain on step v under stirring to obtain a clear solution and;
vii. Purge water for injection and cool down the temperature to 25°C- 30°C and add to above solution and;
viii. Add and mix Sodium metabisulphite under continuous stirring to above solution to obtain a clear solution and
ix. Adjust the pH between 4.5 to 6.50 adjust if required by hydrochloric acid & sodium hydroxide solution and make up the volume up to 500 liters by sterile water for injection
Example-3 Formula for 200 mg/ml Paracetamol Injection
Sr. No.
Ingredient
Per ml qty in percentage
1
Paracetamol
20.00% w/v
16
2
Benzyl Alcohol
4.00% v/v
3
Polyethylene glycol-400
10.0% w/v
4
Propylene glycol
10.0% w/v
5
N-N Dimethyl Acetamide
25.00% v/v
6
Sodium metabisulphite
0.200% w/v
7
Sodium Hydroxide (Pellets)
0.100% w/v
8
Water for Injections
q.s.
Example-4: Formula for 300 mg/mL
Sr. No.
Ingredient
Per ml qty in percentage
1
Paracetamol
30.00%
2
Benzyl Alcohol
4.00
3
Polyethylene glycol-400
10.5%
4
Propylene glycol
11%
5
N-N Dimethyl Acetamide
35%
6
Sodium metabisulphite
0.200
7
Sodium Hydroxide (Pellets)
0.100%
8
Water for Injections
q.s.
Example-5 Comparative Study:
In this comparative study, the present invention was compared with prior art formulations. The formulations were tested for different physiochemical studies. The parenteral solutions were prepared with different solubilizing agents in different ratio.
The present invention F1 comprising Polyethylene glycol-400, Propylene glycol and N-N Dimethyl Acetamide in 1:1:2.8 respectively.
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The formulation T1 comprising Glycofurol as a solubilizing agent without using Polyethylene glycol-400, propylene glycol and N-N Dimethyl acetamide.
The formulation T2 comprising Glycofurol as solubilizing agent in presence of Polyethylene glycol-400 and propylene glycol in absence of N-N Dimethyl acetamide.
The formulation T3 comprising Cremophore as solubilizing agent in presence of Polyethylene glycol-400 and in absence of Propylene glycol.
The formulation T4 doesn’t comprises any solubilizing agent.
The formulation T5 comprises Polyethylene glycol-400, propylene glycol, N-N Dimethyl Acetamide in 2:1:2 respectively.
The formulation T6 comprises Polyethylene glycol-400, propylene glycol, N-N Dimethyl Acetamide in 2:1:5 respectively.
The formulation T7 comprises Polyethylene glycol-400, propylene glycol, N-N Dimethyl Acetamide in 1:1:2 respectively.
Table (a) Comparative study
Sr. No.
Ingredient
F1
(Present invention)
T1
(Prior art)
T2
(Prior art)
T3
(Prior art)
T4
T5
T6
T7
1
Paracetamol
25.00%
25.00%
25%
25%
25%
25%
25%
20%
2
Benzyl Alcohol
4.00%
4.00%
4.00%
25%
10.00%
4.00
5.00%
4%
3
Polyethylene glycol-400
10.0%
absent
10.00%
10%
absent
20.0%
10%
10%
4
Propylene glycol
10.0%
absent
10.00%
absent
absent
10%
5%
10%
5
N-N Dimethyl Acetamide
28.00%
absent
absent
absent
25%
20%
25%
20%
18
6
Sodium Hydroxide (Pellets)
0.100%
0.100%
0.100%
0.10%
0.10%
0.10%
0.1%
0.1%
7
Water for Injections
q.s.
q.s
q.s
q.s
q.s
q.s
q.s
q.s
8
Glycofurol
absent
25%
25%
absent
absent
absent
absent
absent
9
Ethanol
absent
absent
absent
absent
absent
absent
absent
absent
10
Cremophore
absent
absent
absent
2%-5%
absent
absent
absent
absent
Test parameters
Description
A Clear, Colorless solution was obtained.
API was not found to be soluble
API was not found to be soluble
API was not found to be soluble
API was not found to be soluble
A Clear solution was obtained.
A Clear solution was obtained.
A Clear solution was obtained.
Viscosity
18.8 cps
--
--
--
--
--
--
--
pH
5.92
--
--
--
--
5.89
5.82
5.80
Appearance
A Clear, Colorless solution was obtained.
--
--
--
--
A Clear solution was obtained.
A Clear solution was obtained.
A Clear solution was obtained.
Stability at 50oC-60oC
A Clear solution was obtained
--
--
--
--
Crystal formation occurred
Crystal formation occurred
Crystal formation occurred
Stability at 2o-8oC (to be check for crystal formation)
No Crystal formation occurred at 2o-8oC
--
--
--
--
Crystal formation occurred at 2o-8oC
Crystal formation occurred at 2o-8oC
Crystal formation occurred at 2o-8oC
Particulate matter
Free from any Visible Particulate matter
--
--
--
--
Visible Particles were found.
Visible Particles were found.
Visible Particles were found.
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From table a it was observed that solubilizing agent used in prior art i.e. Formulation T1, T2 and T3 shows crystal formulation and it was found that Paracetamol was not soluble in the solubilizing system.
Further it was observed that even if we change the ratio of solubilizing agent in formulation T4-T7 the API was found not to be soluble and even show crystal formulation.
From the above comparative study, it can be inferred that Paracetamol injection was not stabilized using solubilizing agent mentioned in the prior art.
The inventors of the present invention surprisingly found that when solubilizing agent i.e. Polyethylene glycol-400, Propylene glycol and N-N Dimethyl Acetamide was mixed in ratio 1:1:2.8 respectively, the formulation F1 was found to be stable and a clear, colorless solution was obtained.
Example 6: Stability Study:
The cleared aqueous solution of present invention prepared from example-2 was subjected to stability study under different temperature and humidity.
a) Temp. 25°C ± 2° C, 60% RH ± 5% RH
Table (b) Stability study under Temp. 25°C ± 2° C, 60% RH ± 5% RH
Test
Acceptance criteria
Initial Testing
After 3 months
After 6 months
After 9 months
After 12 months
Description
Clear colourless to pale yellow in amber coloured glass ampoule
Clear colorless liquid filled in amber coloured glass ampoule
Clear colorless liquid filled in amber coloured glass ampoule
Clear colorless liquid filled in amber coloured
Clear colorless liquid filled in amber coloured glass ampoule
Clear colorless liquid filled in amber coloured glass ampoule
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glass ampoule
pH
Between 4.50 and 6.50
5.77
5.28
6.22
6.26
6.16
Particulate matter
Solution should be clear and free from foreign particles
Solution is clear and free from foreign particles
Solution is clear and free from foreign particles
Solution is clear and free from foreign particles
Solution is clear and free from foreign particles
Solution is clear and free from foreign particles
Related substance by HPLC
4-Aminophenol
Not more than 0.1%
Not detected
0.01%
0.03%
0.04%
0.003%
4- chloroacetanilide
Not more than 10 ppm
Not detected
Not detected
Not detected
Not detected
Not detected
Single Maximum impurity
Not more than 0.1 %
0.003 %
0.010%
0.009%
0.009%
0.005%
Total impurities
Not more than 0.5 %
0.01%
0.04%
0.05%
0.06%
0.02%
Bacterial endotoxins
Not more than 0.35 EU/mg of paracetamol
Less than 0.35 EU/ mg of paracetamol
NA
NA
NA
NA
Sterility
No microbial growth should be observed
No microbial growth observed
NA
NA
NA
NA
Assay: Each ml contains
Paracetamol: 250 mg/ml
NLT 90.00% to NMT 110.00% of label claimed
100.8%
99.30%
99.36%
99.01%
99.48%
Limit of Ethylene & Diethyl Glycol
Ethylene glycol
Not more than 0.1% w/v
Not detected
NA
NA
NA
NA
Diethylene glycol
Not more than 0.1% w/v
0.00112% w/v
NA
NA
NA
NA
From table (b) it was observed that the aqueous solution of paracetamol was found to be stable and no microbial growth was observed at 25°C ± 2° C, RH 60 % ± 5% RH even after 12 months.
21
b) Temp. 30°C ± 2° C, 75% RH ± 5% RH
Table (c) Stability study under Temp. 30°C ± 2° C, 75% RH ± 5% RH
Test
Acceptance criteria
Initial Testing
After 3 months
After 6 months
After 9 months
After 12 months
Description
Clear colourless to pale yellow in amber coloured glass ampoule
Clear colorless liquid filled in amber coloured glass ampoule
Clear colorless liquid filled in amber coloured glass ampoule
Clear colorless liquid filled in amber coloured glass ampoule
Clear colorless liquid filled in amber coloured glass ampoule
Clear colorless liquid filled in amber coloured glass ampoule
pH
Between 4.50 and 6.50
5.77
5.15
6.22
6.28
6.20
Particulate matter
Solution should be clear and free from foreign particles
Solution is clear and free from foreign particles
Solution is clear and free from foreign particles
Solution is clear and free from foreign particles
Solution is clear and free from foreign particles
Solution is clear and free from foreign particles
Related substance by HPLC
4-Aminophenol
Not more than 0.1%
Not detected
0.01%
0.02%
0.03%
0.02%
4- chloroacetanilide
Not more than 10 ppm
Not detected
Not detected
Not detected
Not detected
Not detected
Single Maximum impurity
Not more than 0.1 %
0.003 %
0.006%
0.008%
0.008%
0.005%
Total impurities
Not more than 0.5 %
0.01%
0.03%
0.04%
0.06%
0.01%
Bacterial endotoxins
Not more than 0.35 EU/mg of paracetamol
Less than 0.35 EU/ mg of paracetamol
NA
NA
NA
NA
Sterility
No microbial growth should be observed
No microbial growth observed
NA
NA
NA
No microbial growth observed
Assay: Each ml contains
22
Paracetamol: 250 mg/ml
NLT 90.00% to NMT 110.00% of label claimed
100.8%
99.52%
99.41%
99.12%
99.71%
Limit of Ethylene & Diethyl Glycol
Ethylene glycol
Not more than 0.1% w/v
Not detected
NA
NA
NA
NA
Diethylene glycol
Not more than 0.1% w/v
0.00112% w/v
NA
NA
NA
NA
From table (c) it was observed that the aqueous solution of paracetamol was found to be stable and no microbial growth was observed at 30°C ± 2° C, 75% RH ± 5% RH ,CLAIMS:An aqueous parenteral composition comprising:
a. An effective amount of active agent that has low aqueous solubility or its pharmaceutically acceptable salt, and
b. a solubilizing mixture consisting of polyethylene glycol, propylene glycol and N, N Dimethyl Acetamide.
2. An aqueous parenteral composition as claimed in 1, wherein the active agents are selected from paracetamol, diclofenac, aceclofenac or any other agent that has low aqueous solubility.
3. An aqueous parenteral composition as claimed in 1, wherein the pH of the aqueous solution is in a range of 4.5 to 6.5
4. An aqueous parenteral solution as claimed in 1 to 4, further comprising one or more pharmaceutically acceptable excipients selected from the group consisting of antioxidants and pH adjusting agent.
5. An aqueous parenteral solution as claimed in 5, wherein antioxidant is sodium metabisulphite.
6. An aqueous parenteral solution as claimed in 5, wherein pH adjusting agent is sodium hydroxide.
7. An aqueous parenteral composition as claimed in 1-2, wherein parenteral composition is in form of aqueous solution comprising:
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a. About 20%-30% w/v of active agent, wherein the active agents can be selected from paracetamonl, diclofenac, aceclofenac or any other active agent having poor aqueous solubility and;
b. About 10 % w/v Polyethylene glycol and;
c. About 10-11 % w/v propylene glycol and;
d. About 25-35 % w/v N-N Dimethyl acetamide and
e. About 0.2 % w/v sodium metabisulphite
8. An aqueous parenteral composition as claimed in 1, comprises
a. About 25.00 % w/v active agent wherein the active agents are selected from paracetamol, Diclofenac or aceclofenac or any other active agents that have low aqueous solubility and;
b. About 10.00 % v/v Polyethylene glycol and;
c. About 10.00 % w/v propylene glycol and;
d. About 28.00 % w/v N-N Dimethyl acetamide and
e. About 0.200% w/v sodium metabisulphite
Wherein Polyethylene glycol, Propylene glycol and N-N Dimethyl Acetamide are present in 1:1:2.8
9. A process of preparing a stable aqueous parenteral solution comprises following steps:
i. Purge the water for injections with the help of nitrogen gas and;
ii. Add and dissolve N-N Dimethylacetamide in step (i) with continuous stirring to get a clear solution and;
iii. Add and mix active agent in solution obtain in step (ii) with continuous stirring to obtain a clear solution and;
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iv. Add and mix benzyl alcohol in solution obtain in step (iii) with continuous stirring to obtain a clear solution and;
v. Add and dissolve propylene glycol in solution obtain in step iv under stirring to obtain a clear solution and;
vi. Add and dissolve polyethylene glycol in solution obtain on step v under stirring to obtain a clear solution and;
vii. Purge water for injection and cool down the temperature to 25°C- 30°C and add to above solution and;
viii. Add and mix Sodium metabisulphite under continuous stirring to above solution to obtain a clear solution and;
ix. Adjust the pH between 4.5 to 6.50 adjust if required by hydrochloric acid & sodium hydroxide solution and make up the volume up to 500 liters by sterile water for injection