This article outlines the uniformity of content for Solid & Liquid dosage forms
Importance
To ensure the consistency of dosage units, each unit in a batch should have a drug substance content within a narrow range around the label claim. Dosage units are defined as dosage forms containing a single dose or a part of a dose of drug substance in each unit. The uniformity of dosage unit’s specification is not intended to apply to suspensions, emulsions, or gels in unit-dose containers intended for external, cutaneous administration.
Definition
The term “uniformity of dosage unit” is defined as the degree of uniformity in the amount of the drug substance among dosage units. Therefore, the requirements chapter apply to each drug substance being comprised in dosage units containing one or more drug substances, unless otherwise specified elsewhere in this Pharmacopeia.
The uniformity of dosage units can be demonstrated by either of two methods, Content Uniformity or Weight Variation (see Table 1). The test for Content Uniformity of preparations presented in dosage units is based on the assay of the individual content of drug substance(s) in a number of dosage units to determine whether the individual content is within the limits set. The Content Uniformity method may be applied in all cases.
The test for Weight Variation is applicable for the following dosage forms:
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(W1) |
Solutions enclosed in unit-dose containers and into soft capsules; |
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(W2) |
Solids (including powders, granules, and sterile solids) that are packaged in single-unit containers and contain no active or inactive added substances. |
|
(W3) |
Solids (including sterile solids) that are packaged in sinunit containers, with or without active or inactive added substances, that have been prepared from true solutions and freeze-dried in the final containers and are labeled to indicate this method of preparation; |
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(W4) |
Hard capsules, uncoated tablets, or film-coated tablets containing 25 mg or more of a drug substance comprising 25% or more, by weight, of the dosage unit or, in the case of hard capsules, the capsule contents, except that uniformity of other drug substances present in lesser proportions is demonstrated by meeting the requirements for Content Uniformity. |
Table 1
Application of Content Uniformity (CU) and Weight Variation (WV) Tests for Dosage Forms
|
Dosage form |
Type |
Subtype |
Dose & ratio of drug substance
|
|
|
25 mg and 25% |
<25 mg or <25% |
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|
Tablets |
Uncoated |
|
WV |
CU |
|
Coated |
Film |
WV |
CU |
|
|
Others |
CU |
CU |
||
|
Capsules |
Hard |
|
WV |
CU |
|
Soft |
Suspensions, emulsion, or gel |
CU |
CU |
|
|
Solutions |
WV |
WV |
||
|
Solids in single unit containers |
Single component |
|
WV |
WV |
|
Multiple components |
Solution freeze dried in final container |
WV |
WV |
|
|
Others |
CU |
CU |
||
|
Solutions in unit dose containers and into soft capsules |
|
|
WV |
WV |
|
Others |
|
|
CU |
CU |
CONTENT UNIFORMITY
Select not fewer than 30 units, and proceed as follows for; the dosage form designated
Where different procedures are used for assay of the preparation and for the Content Uniformity test, it may be necessary to establish a correction factor to be applied to the results of the latter.
Solid Dosage Forms—Assay 10 units individually using an appropriate analytical method. Calculate the acceptance value (see Table 2).
Liquid or Semi-Solid Dosage Forms—Assay 10 units individually using an appropriate analytical method. Carry out the assay on the amount of well mixed material that is removed from an individual container in conditions of normal use, and express the results as delivered dose. Calculate the acceptance value (see Table 2).
Calculation of Acceptance Value—Calculate the acceptance value by the formula:
| M- X | + ks
In which the terms are as defined in Table 2.
Table 2
|
Variable |
Definition |
Conditions |
Value |
|
X |
Mean of individual contents (c1, c2, ¼ , cn), expressed as a percentage of the label claim |
|
|
|
c1, c2, ¼ , cn |
Individual contents of the units tested, expressed as a percentage of the label claim |
|
|
|
N |
Sample size (number of units in a sample) |
|
|
|
K |
Acceptability constant |
If n = 10, then k = |
2.4 |
|
If n = 30, then k = |
2.0 |
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|
S |
Sample standard deviation |
|
(n 1/2 Σ ( - X)2 i=1 / n-1)
|
|
RSD |
Relative standard deviation (the sample standard deviation expressed as a percentage of the mean) |
|
100s/X |
|
M (case 1) to be applied when T ≤ 101.5 |
Reference value |
If 98.5% £X £101.5%, then |
M = X (AV = ks) |
|
If X <98.5%, then |
M = 98.5% (AV = 98.5 – X + ks) |
||
|
If X >101.5%, then |
M = 101.5% (AV = X – 101.5 + ks) |
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|
M (case 2) to be applied when T |
Reference value |
If 98.5 £X £T, then |
M = X (AV = ks) |
|
If X <98.5%, then |
M = 98.5% (AV = 98.5 – X + ks) |
||
|
If X >T, then |
M = T% (AV = X – T + ks) |
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|
Acceptance value (AV) |
|
|
general formula: | M- X | + ks (Calculations are specified above for the different cases.) |
|
L1 |
Maximum allowed acceptance value |
|
L1 = 15.0 unless otherwise specified |
|
L2
|
Maximum allowed range for deviation of each dosage unit tested from the calculated of M |
On the low side, no dosage unit result can be less than value [1–(0.01)(L2)]M, while on the high side no dosage unit result can be greater than [1 + (0.01)(L2)]M. (This is based on an L2 value of 25.0.) |
L2 = 25.0 unless otherwise specified
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|
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T Target content per dosage unit at the time of manufacture, expressed as a percentage of the label claim |
|
|
Uniformity of content, acceptability constant, weight variation, uniformity of dosage unit
