Optics: measuring and testing – For light transmission or absorption – By comparison
Reexamination Certificate
2000-03-07
2002-03-26
Font, Frank G. (Department: 2877)
Optics: measuring and testing
For light transmission or absorption
By comparison
C356S394000
Reexamination Certificate
active
06362891
ABSTRACT:
TECHNICAL FIELD AND BACKGROUND ART
The present invention relates to powder analysis and is particularly concerned with a method of analysing powder formed as a mixture of ingredients and derived from a bulk preparation of such a powder.
The present invention was primarily, but not essentially, developed for use in the pharmaceutical industry where it is conventional practice in the commercial production of a product which is, or is to be derived from, a powder for the ingredients of that powder to be loaded into a mixing chamber where they are tumbled or otherwise agitated to ensure thorough mixing of the ingredients. For a pharmaceutical product, the powdered ingredients loaded into the chamber will be one or more active ingredients and one or more excipients. In a typical pharmaceutical facility, the bulk powder mixture will be in the order of 1000 kg and will be intended for sub-division, usually into small containers convenient for retail purposes, into capsules for individual doses of the powder or for processing into individual dose tablets.
Irrespective of the manner in which the bulk powder from the mixing chamber is subsequently processed to be presented for use or retail purposes, in the pharmaceutical industry there are statutory requirements that the ingredients in the form of the pharmaceutical or chemical constituents in end product (typically powder, capsules, or tablets as aforementioned) as presented for retail purposes or use are dispersed uniformly throughout the material of the end product to ensure that dose formulations are identical within prescribed tolerances.
As a consequence, pharmaceutical products derived from powder are subjected to a qualitative and quantitative control analysis, principally to ensure that the end product has required chemical constituents, that the proportions of the required chemical constituents are correct and that the chemical constituents are dispersed uniformly throughout the end product. Where the bulk powder is processed into individual dose tablets, a conventional form of quality control is to subject tablets randomly selected from a production batch to spectrophotometric analysis where a beam of electromagnetic radiation (usually near infrared—NIR) is directed to and transmitted through the selected sample tablet for the transmitted beam to be detected and analysed. From variations in the absorption characteristics exhibited by the ingredients (chemical/pharmaceutical constituents) of the tablet to the applied radiation beam as measured by the detector, it is possible in known manner to effect the required qualitative and quantitative analysis.
Techniques for analysing tablets by NIR spectrophotometric transmission measurements are disclosed in our patent specification EP-A-0,896,215 and in EP-A-0767369.
Once production has started to sub-divide a bulk powder mixture into discrete weights or doses and to package those doses typically into capsules or to press them into tablets, production rates are so fast that if analysis of the final product indicates that the ingredients, particularly active ingredients, are not uniformly dispersed throughout the bulk powder mixture, there is likely to be considerable wastage and expense (both in materials and in production), in the products which were made prior to a decision to stop production.
As a consequence (and in some countries it is a statutory requirement in the production of pharmaceutical products from powder mixtures), it is conventional practice to analyse samples of powder derived from the bulk mixture in the mixing chamber to ensure appropriate homogenity and concentration of the active and excipient ingredients within the bulk mixture before its sub-division commences. For this analysis several powder samples are taken from the bulk mixture at locations spaced from each other and at various depths in the mixture to give an overall picture of how well the ingredients are homogenised throughout the blend or mix.
Each powder sample that is removed from the bulk powder mixture is assessed for homogenity of its ingredients and conventionally this is achieved by either of two well-known techniques. The longest standing and probably most utilised technique is that of high performance liquid chromatography (HPLC) which is well-known in the art and as such need not be discussed in detail. However despite its popularity, it is recognised that HPLC has distinct disadvantages notably a) it utilises toxic solvents and therefore it has to be used in a facility remote from the chemical/pharmaceutical manufacturing facility for good manufacturing practice, b) the analysis can take many hours or days by experienced personnel with consequent expense and delays in production time, and c) it is suitable only for determining concentration throughout the mixture of the or a particular active ingredient in the mixture.
The second technique is spectrophotometric analysis of the powder sample by reflectance measurements of a near infrared (NIR) beam. For each sample, a tablet dose weight is weighed into a glass vial or other container and the sample is then scanned. The sample is then mixed and scanned again—this procedure is repeated five times and the resultant spectra are then averaged. Spectrophotometric analysis of powder by reflectance measurements is discussed in connection with our patent publication WO 95/00831. The tablet dose weight is used for the analysis (although up to three times such a dose weight is permitted for the analysis) in accordance with regulations laid down by recognised pharmaceutical bodies on the basis that if a much larger weight from the sample is used, it could suggest that a mixture is properly homogenised when in fact it is not. The sample is scanned five times due the nature of the depth of penetration of the NIR light beam. Tests have shown that using standard NIR reflectance optics, the NIR beam will only pass into a fine white powder up to a depth of 0.5 mm. As a consequence, to get a representative view and useable cross section of the whole sample, the powder has to be mixed and scanned five times and the resultant spectra averaged. Homogenity of the mixture is then usually determined by calculating the standard deviation of the samples at absorption characteristics which are unique to the active ingredient or ingredients. The numerous scanning and re-mixing of powder from each sample is a lengthy procedure which causes consequential delays in production and is preferably carried out by experienced laboratory personnel. Overall therefore this second technique of analysis is generally regarded as expensive and of suspect accuracy due to the inability of the NIR beam to scan efficiently a relatively thick surface layer of powder.
From the foregoing, it will be realised that there is a need to provide a method of analysing powder formed from a mixture of ingredients and prepared in bulk (particularly but not essentially for pharmaceutical and/or chemical products) and which method alleviates the disadvantages of the above described prior proposals. It is an object of the present invention to satisfy this need. More particularly, the present invention has as its aims to provide a method of analysing powder formed as a mixture of ingredients and derived from a bulk preparation which permits a fast analysis that may be used efficiently by inexperienced personnel to alleviate personnel error and delays in production and to provide an accurate analysis on the basis of which an assessment can be made on the acceptability or otherwise of the homogenity and concentration of either or both active ingredients and excipients in the bulk powder mixture or blend.
STATEMENT OF INVENTION
According to the present invention, there is provided a method of analysing powder formed as a mixture of ingredients and derived from a bulk preparation thereof which comprises predetermining an assay standard spectrum for a relevant ingredient of the bulk powder mixture by spectrophotometrically analysing characteristics of that relevant ingredient from transmission measurements o
Axon Tony Graham
Hammond Stephen Victor
Benson Gregg C.
Font Frank G.
Goddard Carl J.
Pfizer Inc.
Richardson Peter C.
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