inprocess as per usp ip bp liquid dosage forms

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Liquid dosage Liquid dosage forms forms

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Page 1: Inprocess as per usp ip bp liquid dosage forms

Liquid dosage Liquid dosage formsforms

Page 2: Inprocess as per usp ip bp liquid dosage forms

Introduction Introduction Oral Liquids are homogeneous liquid preparations, usually consisting of a Oral Liquids are homogeneous liquid preparations, usually consisting of a

solution, an emulsion or a suspension of one or more medicaments in a solution, an emulsion or a suspension of one or more medicaments in a suitable vehicle. They are intended for oral administration either undiluted or suitable vehicle. They are intended for oral administration either undiluted or after dilution. after dilution.

They may contain auxiliary substances such as suitable dispersing, They may contain auxiliary substances such as suitable dispersing, emulsifying, suspending, wetting, solubilising, thickening, stabilizing agents emulsifying, suspending, wetting, solubilising, thickening, stabilizing agents and antimicrobial preservatives. and antimicrobial preservatives.

They may also contain suitable sweetening, flavoring and permitted coloring They may also contain suitable sweetening, flavoring and permitted coloring agents; if saccharin, including its sodium and potassium salts, is used as a agents; if saccharin, including its sodium and potassium salts, is used as a sweetening agent, its concentration in preparations meant for pediatric use sweetening agent, its concentration in preparations meant for pediatric use should be restricted so as to limit its intake to 5 mg per kg of body weight.should be restricted so as to limit its intake to 5 mg per kg of body weight.

During manufacture, packaging, storage and distribution of During manufacture, packaging, storage and distribution of oral liquids, suitable means shall be taken to ensure their oral liquids, suitable means shall be taken to ensure their microbial quality; acceptance criteria for microbial quality microbial quality; acceptance criteria for microbial quality are given in Chapter 5.9 Microbial Quality of Preparationsare given in Chapter 5.9 Microbial Quality of Preparations

Oral Liquids are variously known as Elixirs, Linctuses Oral Liquids are variously known as Elixirs, Linctuses Mixtures, Oral Drops, Oral Emulsions, Oral Solutions, Oral Mixtures, Oral Drops, Oral Emulsions, Oral Solutions, Oral Suspensions and Syrups. These terms are defined belowSuspensions and Syrups. These terms are defined below

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Different form of oral liquid Different form of oral liquid Elixirs:Elixirs: Elixirs are clear, flavored Oral Liquids containing one or more Elixirs are clear, flavored Oral Liquids containing one or more

active ingredients dissolved in a vehicle that usually contains a high active ingredients dissolved in a vehicle that usually contains a high proportion of Sucrose or a suitable polyhydric alcohol or alcohols and may proportion of Sucrose or a suitable polyhydric alcohol or alcohols and may also contain Ethanol (95 per cent) or a dilute Ethanol.also contain Ethanol (95 per cent) or a dilute Ethanol.

Linctuses:Linctuses: Linctuses are viscous Oral Liquids containing one or more Linctuses are viscous Oral Liquids containing one or more active ingredients dissolved in a vehicle that usually contains a high active ingredients dissolved in a vehicle that usually contains a high proportion of sucrose, other sugars or a suitable polyhydric alcohol or proportion of sucrose, other sugars or a suitable polyhydric alcohol or alcohols. Linctuses are intended for use in the treatment or relief of cough, alcohols. Linctuses are intended for use in the treatment or relief of cough, and are sipped and swallowed slowly without the addition of water.and are sipped and swallowed slowly without the addition of water.

Mixtures:Mixtures: Mixtures are Oral Liquids containing one or more active Mixtures are Oral Liquids containing one or more active ingredients dissolved, suspended or dispersed in a suitable vehicle. ingredients dissolved, suspended or dispersed in a suitable vehicle. Suspended solids may separate slowly on keeping but are easily Suspended solids may separate slowly on keeping but are easily redispersed on shaking.redispersed on shaking.

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Different form of oral liquid Different form of oral liquid Cont.Cont. Oral Emulsions:Oral Emulsions: Oral Emulsions are Oral Liquids containing one or more Oral Emulsions are Oral Liquids containing one or more

active ingredients and are stabilized oil-in-water dispersions, either or both active ingredients and are stabilized oil-in-water dispersions, either or both phases of which may contain dissolved solids. Solids may also be phases of which may contain dissolved solids. Solids may also be suspended in Oral Emulsions. Emulsions may exhibit phase separation but suspended in Oral Emulsions. Emulsions may exhibit phase separation but are easily reformed on shaking. The preparation remains sufficiently stable are easily reformed on shaking. The preparation remains sufficiently stable to permit a homogeneous dose to be withdrawn.to permit a homogeneous dose to be withdrawn.

Oral Solutions:Oral Solutions: Oral Solutions are Oral Liquids containing one or more Oral Solutions are Oral Liquids containing one or more active ingredients dissolved in a suitable vehicle.active ingredients dissolved in a suitable vehicle.

Oral Suspensions:Oral Suspensions: Oral Suspensions are Oral Liquids containing one or Oral Suspensions are Oral Liquids containing one or more active ingredients suspended in a suitable vehicle. Suspended solids more active ingredients suspended in a suitable vehicle. Suspended solids may slowly separate on keeping but are easily redispersed. In the may slowly separate on keeping but are easily redispersed. In the manufacture of oral suspensions containing dispersed particles, measures manufacture of oral suspensions containing dispersed particles, measures shall be taken to ensure a suitable and controlled particle size with regard shall be taken to ensure a suitable and controlled particle size with regard to the intended use of the product.to the intended use of the product.

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Different form of oral liquid Different form of oral liquid Cont.Cont. Syrups:Syrups: Syrups are viscous Oral Liquids that may contain one or more Syrups are viscous Oral Liquids that may contain one or more

active ingredients in solution. The vehicle usually contains large amounts active ingredients in solution. The vehicle usually contains large amounts of Sucrose or other sugars to which certain polyhydric alcohols may be of Sucrose or other sugars to which certain polyhydric alcohols may be added to inhibit crystallization or to modify solubilisation, taste and other added to inhibit crystallization or to modify solubilisation, taste and other vehicle properties. Sugarless syrups may contain sweetening agents and vehicle properties. Sugarless syrups may contain sweetening agents and thickening agents. Syrups may contain Ethanol (95%) as a preservative or thickening agents. Syrups may contain Ethanol (95%) as a preservative or as a solvent to incorporate flavoring agents. Antimicrobial agents may also as a solvent to incorporate flavoring agents. Antimicrobial agents may also be added to Syrups.be added to Syrups.

Oral Drops:Oral Drops: Oral Drops are Oral Liquids that are intended to be Oral Drops are Oral Liquids that are intended to be administered in small volumes with the aid of a suitable measuring device administered in small volumes with the aid of a suitable measuring device such as a dropper.such as a dropper.

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Liquid dosage formsLiquid dosage forms

Monophasic liquid D.FSolutions Polyphasic liquid D.F

Aqueous solutions Non-aqueous solutions

Suspensions Colloids

Emulsions

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Liquid dosage Liquid dosage formsforms

■ ■ Solutions: solutions are clear liquid preparations Solutions: solutions are clear liquid preparations containing one or more active ingredients dissolved in a containing one or more active ingredients dissolved in a suitable vehicle.suitable vehicle.

■ ■ Suspensions (Solid in liquid dispersion): liquid Suspensions (Solid in liquid dispersion): liquid preparations containing one or more active ingredients preparations containing one or more active ingredients suspended in a suitable vehicle.suspended in a suitable vehicle.

■ ■ Emulsions (liquid in liquid dispersion): emulsions are two Emulsions (liquid in liquid dispersion): emulsions are two phase system in which one liquid is dispersed throughout phase system in which one liquid is dispersed throughout another liquid in the form of small particles.another liquid in the form of small particles.

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■ ■ Colloids: A system in which finely divided Colloids: A system in which finely divided particles, which are approximately less than 1 particles, which are approximately less than 1 µm in size, are dispersed within a continuous µm in size, are dispersed within a continuous medium in a manner that prevents them from medium in a manner that prevents them from being filtered easily or settled rapidly.being filtered easily or settled rapidly.

Liquid dosage Liquid dosage formsforms

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Advantages of liquid Advantages of liquid dosage formdosage form

Liquids are easier to swallow therefore easier for Liquids are easier to swallow therefore easier for children, old age and unconscious people.children, old age and unconscious people.

A drug must be in solution before it can be A drug must be in solution before it can be absorbed (more quickly effective than and oral absorbed (more quickly effective than and oral liquids)liquids)

A A solutionsolution is an homogenous system, the drug will is an homogenous system, the drug will be uniformly distributed throughout the be uniformly distributed throughout the preparation (uniform dose than suspension and preparation (uniform dose than suspension and emulsion which need shaking)emulsion which need shaking)

Some drugs can irritate the gastric mucosa if Some drugs can irritate the gastric mucosa if localized in one area. Irritation is reduced by localized in one area. Irritation is reduced by administration of a solution of the drugadministration of a solution of the drug

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Problem associated with the manufacturing of solutions Problem associated with the manufacturing of solutions disadvantages of solutionsdisadvantages of solutions

Liquids are Liquids are bulkybulky and inconvenient to transport and store and inconvenient to transport and store The The stabilitystability of ingredients in aqueous solution is often of ingredients in aqueous solution is often

poor than in solid dosage formpoor than in solid dosage form Solution provide suitable media for the growth of micro-Solution provide suitable media for the growth of micro-

organisms and may require the addition of organisms and may require the addition of preservativepreservative Accurate dose measuring depends on the ability of patient Accurate dose measuring depends on the ability of patient

to measure the dose (needs an accurate spoon to measure to measure the dose (needs an accurate spoon to measure the dose)the dose)

The The tastetaste of a drug is always pronounced when it in of a drug is always pronounced when it in solution (unpleasant taste or odours are difficult to mask)solution (unpleasant taste or odours are difficult to mask)

Major signs of instability: color change, precipitation, Major signs of instability: color change, precipitation, microbial growth, chemical gas formation.microbial growth, chemical gas formation.

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TestsTests Uniformity of contentUniformity of content Uniformity of volumeUniformity of volume Microbial Quality of PreparationsMicrobial Quality of Preparations

DescriptionDescription pHpH Sealing of capsSealing of caps Leak testLeak test

Pharmacopoial

Non- Pharmacopoial

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This test is applicable to single dose liquid in suspension form or liquid that This test is applicable to single dose liquid in suspension form or liquid that contain contain less thanless than 10 mg or less than 10 per cent w/w of active ingredient (As 10 mg or less than 10 per cent w/w of active ingredient (As per IP)per IP). .

This test is applicable to oral liquid that contain This test is applicable to oral liquid that contain less than 25 mg or less than less than 25 mg or less than 25 per cent w/w of active ingredient (As per BP/USP )25 per cent w/w of active ingredient (As per BP/USP )..

For oral liquid containing more than one active ingredient carry out the test For oral liquid containing more than one active ingredient carry out the test for each active ingredient that corresponds to the aforementioned conditions. for each active ingredient that corresponds to the aforementioned conditions.

The test for Uniformity of content should be carried out only after the content The test for Uniformity of content should be carried out only after the content of active ingredient(s) in a pooled sample of the oral liquid has been shown to of active ingredient(s) in a pooled sample of the oral liquid has been shown to be within accepted limits of the stated content.be within accepted limits of the stated content.

The test for Uniformity of content is not applicable to capsule containing The test for Uniformity of content is not applicable to capsule containing multivitamins and trace elements multivitamins and trace elements (BP/(BP/

Uniformity of content (IP/BP)Uniformity of content (IP/BP)

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Method.Method. Determine the content of active ingredient(s) in each of 10 dosage units taken Determine the content of active ingredient(s) in each of 10 dosage units taken

at random using the method given in the monograph or by any other suitable at random using the method given in the monograph or by any other suitable analytical method.analytical method.

Acceptance limitsAcceptance limits The preparation complies with the test if the individual values thus obtained The preparation complies with the test if the individual values thus obtained

are all between 85 to 115 per cent of the average value. are all between 85 to 115 per cent of the average value.

The preparation fails to comply with the test if more than one individual The preparation fails to comply with the test if more than one individual contents are outside the limits of 85 to 115 per cent of the average value or if contents are outside the limits of 85 to 115 per cent of the average value or if one individual contents are outside the limits of 75 to 125 per cent of the one individual contents are outside the limits of 75 to 125 per cent of the average content.average content.

Uniformity of content (IP/BP) Uniformity of content (IP/BP)

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If one individual contents are outside the limits of 85 to 115 per cent of the If one individual contents are outside the limits of 85 to 115 per cent of the average content but within the limits of 75 to 125 per cent, repeat the average content but within the limits of 75 to 125 per cent, repeat the determination using another 20 dosage units. determination using another 20 dosage units.

The preparation complies with the test if not more than three individual The preparation complies with the test if not more than three individual contents of the total sample of 30 dosage units are outside the limits of 85 to contents of the total sample of 30 dosage units are outside the limits of 85 to 115 per cent of the average content and not more than one is outside the limits 115 per cent of the average content and not more than one is outside the limits of 75 to 125 per cent of the average content.of 75 to 125 per cent of the average content.

Uniformity of contents (IP/BP)Uniformity of contents (IP/BP)

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Uniformity of container contents / Uniformity of container contents / Contents of Packaged Dosage Forms (IP)Contents of Packaged Dosage Forms (IP)

The following tests and specifications apply to oral dosage forms and The following tests and specifications apply to oral dosage forms and preparations intended for topical use that are packaged in containers in preparations intended for topical use that are packaged in containers in which the labeled net quantity is not more than which the labeled net quantity is not more than 100 g or 300 ml or 1000 100 g or 300 ml or 1000 units,units, as the case may be as the case may be

For higher labeled quantities the test and limits given in the standards of For higher labeled quantities the test and limits given in the standards of Weights and Measures (Packaged commodities) Rules, 1977 may be Weights and Measures (Packaged commodities) Rules, 1977 may be followed.followed.

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Contents of Packaged Dosage FormsContents of Packaged Dosage Forms Test MethodTest Method For Viscous preparations:For Viscous preparations: Select a sample of 10 filled containers and Select a sample of 10 filled containers and

determine the weight determine the weight of the contents of each container as directed under of the contents of each container as directed under Ointments, Creams, Pastes, Granules and Powders for Oral Liquids. Ointments, Creams, Pastes, Granules and Powders for Oral Liquids. Determine the weight per ml Determine the weight per ml and calculate the net volume of the contents of and calculate the net volume of the contents of each container.each container.

Non-viscous and free-flowing liquids:Non-viscous and free-flowing liquids: Pour completely the contents of each Pour completely the contents of each container into calibrated volume measures of the appropriate size and container into calibrated volume measures of the appropriate size and determine the volume of the contents of the 10 containers.determine the volume of the contents of the 10 containers.

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Contents of Packaged Dosage FormsContents of Packaged Dosage Forms The average net volume of the contents of the 10 containers is not less than The average net volume of the contents of the 10 containers is not less than

the labelled amount, and the net volume of the contents of any single the labelled amount, and the net volume of the contents of any single containers is containers is

not less than 91 per cent and not more than 109 percent not less than 91 per cent and not more than 109 percent of the labelled of the labelled amount where the labelled amount is amount where the labelled amount is 50 ml or less 50 ml or less

not less than 95.5 per cent and not more than 104.5 percent not less than 95.5 per cent and not more than 104.5 percent of the labelled of the labelled amount where the labelled amount is amount where the labelled amount is more than 50 ml but not more than 200 more than 50 ml but not more than 200 ml ml

not less than 97 per cent but not more than 103 percent not less than 97 per cent but not more than 103 percent of the labelled of the labelled amount where the labelled amount is amount where the labelled amount is more than 200 ml but not more than more than 200 ml but not more than 300 ml300 ml

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Test as per USPTest as per USP Deliverable volume Deliverable volume To ensure that deliver the volume of dosage To ensure that deliver the volume of dosage

form that is declared on the labelform that is declared on the label Apply for both liquid preparation and liquid Apply for both liquid preparation and liquid

preparation that are constituted from soild preparation that are constituted from soild upon addition of a designated volume of upon addition of a designated volume of specific diluentsspecific diluents

Not for single unit containers when Not for single unit containers when monograph include the test for uniformity of monograph include the test for uniformity of unit unit

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Deliverable volume Deliverable volume cont.cont. Method:Method: First determine the density of the liquid (if First determine the density of the liquid (if

required )required ) Select NLT 30 containers and proceed Select NLT 30 containers and proceed

o For oral solution and oral susp.: shakeFor oral solution and oral susp.: shakeo For powder : reconstitute as directed For powder : reconstitute as directed

Discharge the containers contents into suitable Discharge the containers contents into suitable tared container (5s unit dosage, 10s multi tared container (5s unit dosage, 10s multi dosage)dosage)

Determine mass and determine volume using Determine mass and determine volume using density density

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Deliverable volume Deliverable volume cont.cont. Method:Method: Determine volume by pouring content into dry graduated Determine volume by pouring content into dry graduated

measuring cylindermeasuring cylinder Acceptance criteriaAcceptance criteria For multiple –unit container: 10 unit For multiple –unit container: 10 unit AVG: NLT 100 % AVG: NLT 100 % Any container NLT 95 % Any container NLT 95 % If A avg vol is less than 100 % but contain of all 10 is more If A avg vol is less than 100 % but contain of all 10 is more

than 95 %than 95 % B if avg. vol. is NLT 100 % & vol of NMT 1 container is Less B if avg. vol. is NLT 100 % & vol of NMT 1 container is Less

than 95 % but not less than 90 %than 95 % but not less than 90 % Perform test of additional 20 container Perform test of additional 20 container Avg of 30 is NLT 100 % & vol of NMT 1 out of 30 container Avg of 30 is NLT 100 % & vol of NMT 1 out of 30 container

is Less than 95 % but not less than 90 %is Less than 95 % but not less than 90 %

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Deliverable volume Deliverable volume cont.cont. Acceptance criteriaAcceptance criteria For Unit-container: 10 unit For Unit-container: 10 unit AVG: NLT 100 % AVG: NLT 100 % Any container between 95 %-110 % Any container between 95 %-110 % If A avg vol is less than 100 % but contain of all 10 is between If A avg vol is less than 100 % but contain of all 10 is between

95 %-110 % 95 %-110 % B if avg. vol. is NLT 100 % & vol of NMT 1 container is B if avg. vol. is NLT 100 % & vol of NMT 1 container is

outside between 95 %-110 % but not out side of between 90 outside between 95 %-110 % but not out side of between 90 %-115 % %-115 %

Perform test of additional 20 container Perform test of additional 20 container Avg of 30 is NLT 100 % & vol of NMT 1 container is outside Avg of 30 is NLT 100 % & vol of NMT 1 container is outside

between 95 %-110 % but not out side of between 90 %-115 % between 95 %-110 % but not out side of between 90 %-115 %

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Test as per BPTest as per BP Uniformity of dosage form: Uniformity of dosage form: single dose containers uniformity single dose containers uniformity

of mass and uniformity of contentof mass and uniformity of content

Uniformity of content:Uniformity of content: Single dose preparation (susp.) or as Single dose preparation (susp.) or as mentioned in monograph Already discussedmentioned in monograph Already discussed

Uniformity of mass:Uniformity of mass: single dose preparation (sol & emul.) are single dose preparation (sol & emul.) are solution or emulsion comply with the following test: solution or emulsion comply with the following test:

Weight 20 container & determine avg massWeight 20 container & determine avg mass NML 2 individual mass deviate more than 10 % of avg mass and NML 2 individual mass deviate more than 10 % of avg mass and

not by more than 20 %not by more than 20 %

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Dose and uniformity of Dose and uniformity of dose of oral dropsdose of oral drops

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Microbial quality of preparation (IP)Microbial quality of preparation (IP) This chapter provides acceptance criteria for the This chapter provides acceptance criteria for the

microbiological microbiological quality of pharmaceutical productsquality of pharmaceutical products. They are . They are not mandatory requirements.not mandatory requirements.

If microorganism are present in a pharmaceutical If microorganism are present in a pharmaceutical preparation, they can reduce or inactivate the therapeutic preparation, they can reduce or inactivate the therapeutic activity of the product or can adversely affect the health of activity of the product or can adversely affect the health of the patient. Hence pharmaceutical preparation should have the patient. Hence pharmaceutical preparation should have low bio-burden and they should not have specified low bio-burden and they should not have specified microorganism which are harmful. microorganism which are harmful.

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Microbial quality of preparation Microbial quality of preparation (BP/USP)(BP/USP)

The presence of certain micro-organisms in non-sterile The presence of certain micro-organisms in non-sterile preparations may have the potential to reduce or even preparations may have the potential to reduce or even inactivate the therapeutic activity of the product and has a inactivate the therapeutic activity of the product and has a potential to adversely affect the health of the patient. potential to adversely affect the health of the patient. Manufacturers therefore have to ensure a low bio-burden of Manufacturers therefore have to ensure a low bio-burden of finished dosage forms by implementing current guidelines on finished dosage forms by implementing current guidelines on Good Manufacturing Practice during the manufacture, storage Good Manufacturing Practice during the manufacture, storage and distribution of pharmaceutical preparations. and distribution of pharmaceutical preparations.

Acceptance criteria for non-sterile pharmaceutical products Acceptance criteria for non-sterile pharmaceutical products based upon the total aerobic microbial count (TAMC) and the based upon the total aerobic microbial count (TAMC) and the total combined yeasts/moulds count (TYMC) are given in Tablestotal combined yeasts/moulds count (TYMC) are given in Tables

When an acceptance criterion for microbiological quality is When an acceptance criterion for microbiological quality is prescribed it is interpreted as follows: prescribed it is interpreted as follows:

 —  — 101011 CFU: maximum acceptable count = 20; CFU: maximum acceptable count = 20;  —  — 101022 CFU: maximum acceptable count = 200; CFU: maximum acceptable count = 200;  —  — 101033 CFU: maximum acceptable count = 2000, and so forth CFU: maximum acceptable count = 2000, and so forth