Tài liệu Pharmaceutical Coating Technology (Part 3) pdf

Page 53 Sugar coating John E.Hogan SUMMARY The chapter commences with a brief introduction to the technique of sugar coating, which includes a note on the advantages and disadvantages of this method of coating The various sequential steps involved in sugar coating are covered in some detail, i.e sealing, subcoating, smoothing, colour coating, polishing and printing In the section dealing with subcoating several suitable formulations are provided with details regarding application Traditionally the colour-coating step in sugar coating has received much attention as the aesthetics of this dosage form are most important Accordingly this section provides considerable depth, including a comparison of previously utilized water-soluble colour systems with modern pigment coloured systems A description of sugar coating faults emphasizes the need for adequate drying conditions during the process to prevent a build up of residual moisture within the tablet Problems of sucrose inversion and difficulties in polishing are also covered The chapter concludes with a consideration of how the process of sugar coating tablet Problems of sucrose inversion and difficulties in polishing are also covered The chapter concludes with a consideration of how the process of sugar coating can affect the dissolution and stability behaviour of the dosage form 3.1 INTRODUCTION The pharmaceutical process of sugar coating remains a widely practised technology despite the interest arising from film-coating techniques since the 1950s However, it is true to say, as has been indicated in Chapter 1, that the technology of sugar coating has remained relatively static while attention has been focused increasingly on film coating Page 54 3.2 BASIC PROCESS REVIEW Unlike film coating, sugar coating is still a multistep process Its use of labour is more intensive than in film coating and process operators require a fair degree of skill but less than in former days when more traditional methods prevailed In suitable sugar-coating equipment the tablet cores are successively treated with aqueous sucrose solutions which, depending on the stage of coating reached, may contain other functional ingredients, e.g fillers, colours, etc The build up of coating material is due to a transference of coating medium from one tablet to another Typically a single liquid application will be made which will be allowed to spread over the entire tablet bed utilizing the mixing capability of the particular equipment At this point, drying, usually in the form of heated air, will be used to dry the application The whole cycle will then be successively repeated In this respect sugar coating differs from film coating as in this process each tablet passes through a zone of application which is subject to rapid and continuous drying 3.3 ADVANTAGES OF SUGAR COATING Despite the undoubted disadvantages of the sugar-coating process in terms of process length, intensive operator attention and so forth, it is important to be aware that sugar coating can have certain advantages: • It utilizes inexpensive and readily available raw materials • Constituent raw materials are widely accepted—no regulatory problems • Modern, simplified techniques have greatly reduced coating times over traditional sugar-coating methods • No complex equipment or services are required • The process is capable of being controlled and documented to meet modern GMP standards • Simplicity of equipment and ready availability of raw materials make sugar coating an ideal coating method for developing countries • The process is generally not as critical as film coating; recovering and reworking procedures are usually possible • For high humidity climates, it generally offers a stability advantage over film-coated tablets • Results are aesthetically pleasing and have wide consumer acceptability • Tablet cores may generally be softer than those demanded by film coating, especially those for aqueous film coating 3.4 THE STAGES IN SUGAR COATING 3.4.1 Sealing It is necessary to protect the tablet core from the aqueous nature of sucrose applications to follow Sealing also prevents certain types of materials from migrating to Page 55 Fig 3.1 The stages in sugar coating the tablet surface and spoiling the appearance, e.g oils, acids, etc This is unfortunately an organic solvent-dependent step in an otherwise aqueous process A film of water-impervious polymer is built up using materials such as: • • • • Shellac CAP PVAP Zein Shellac has all the disadvantages of a natural material (see Chapter for a more detailed description), the other polymers used tend to be those which have an additional use as enteric-coating materials so that they should be applied only in sufficient quantity to form an efficient seal A lamination process, whereby an application of sealant is followed by an application of dusting power, e.g talc, is nearly always used 3.4.2 Subcoating During the sugar-coating process the increase in weight achieved can be 30–50% of the weight of the original tablet core Much of the added weight is applied at the subcoating stage Subcoating serves to confer on the tablet core a perfectly rounded aspect The ideal shape for sugar coating is a deeply convex core with minimal edges (Fig 3.2) This condition will obviously require less coating material than where the tablet edge is comparatively thick Seager et al (1985) have cautioned that deeply convex tablet cores may not be exactly ideal as their crowns tend to be soft Basically there are two methods: Page 56 Lamination process Below are illustrated two typical examples of binder solution formulations for subcoating, together with their corresponding dusting powder formulations The principle of the process is that a volume of binder solution is applied to the sealed cores in the coating pan Once this has spread over the tablet bed an application of powder is dusted into the pan, and when this has evenly distributed itself over the contents, drying air is applied The drying air process needs to be carefully controlled to prevent too rapid evaporation of the water The objective should be to create as smooth a coat as possible in order to reduce the time for smoothing the coat in the final stages of process Excessively rapid drying results in a very uneven surface Too low an evaporation rate gives rise to a lengthy process and the danger of cores adhering together Fig 3.2 Ideal and non-ideal tablet core shapes for sugar coating Page 57 Binder solution formulation: I(% w/w) 3.3 8.7 55.3 to 100.0 I(% w/w) 40.0 5.0 25.0 28.0 2.0 Gelatin Gum acacia (powdered) Sucrose Water Dusting powder formulation: Calcium carbonate Titanium dioxide Talc Surcose (powdered) Gum acacia (powdered) Features of the lamination process II(% w/w) 6.0 8.0 45.0 to 100.0 II(% w/w) — 1.0 61.0 38.0 — • The use of a binder solution with gum binds the powder application on the tablet • Utilizes inexpensive ingredients with high opacity • In skilled hands a very fast build up to the required shape is obtained Disadvantages of the lamination process • The use of free dusted powders tends to create clean-up problems • Difficult to control in documentary terms as frequently volumes note weights of powders are specified • Difficult to automate as both powders and liquids are involved Suspension process In recent years, automation in the sugar-coating process has required the use of a liquid subcoat These are generally suspensions of the filler materials, e.g calcium carbonate, talc, sucrose in the gum solutions The example quoted below is suitable for hand panning or automatic methods with a little modification A description of a typical sugar-coating pan is given and the latest type of side-vented coating pans is given in Chapter The system contains only approximately 23% water and consequently dries quickly Formulae Quantities are for a batch of 250 000 tablets having an average weight of 200 mg and providing a batch weight of 50 kg in a ft diameter pan Coating powder: Calcium carbonate, light Talc 6.8 kg 1.8 kg Page 58 Starch, pulverized Titanium dioxide 1.0 kg 0.4 kg The powders are mixed in a simple blender (e.g V-section type) and sifted through a 60 mesh screen Subcoat Syrup: Water Dextrin Sucrose 10.0 kg 0.5 kg 22.5 kg The dextrin is dissolved in the water and the resultant solution boiled; the sucrose is then added and stirred until dissolved Two applications of this clear syrup are made prior to adding kg of coating powder to the remaining syrup before commencing the subcoating 3.4.3 Smoothing The product at the end of the subcoating will be too rough to continue with colour coating Smoothing is usually achieved by applications of plain 70% w/w syrup However large degrees of unevenness will require some subcoating solids in the initial smoothing coats Typically, however, if subcoating is carried out well, then approximately ten applications of 70% syrup will be required for tablets that are suitable for the next stage 3.4.4 Colour coating This is one of the most important steps in the sugar-coating process as it has immediate visual impact During this step the coating syrup contains the colour solids necessary to achieve the desire shade Water-soluble dyes were used previously as colouring agents for sugar-coated tablets This has largely been superseded by the use of modern water-insoluble pigment forms including the aluminium lakes of the water-soluble colours Here, the water-soluble dye is adsorbed onto a hydrated alumina surface, filtered, washed and dried By careful processing, the optimum particle size profile is achieved The smaller and more even the particle size, the greater the colouring power and hence the smaller the quantity that need be used to achieve the same result These lake pigments are essentially insoluble in aqueous systems between pH 3.5 and 9.0 and find important uses in tablet coatings both using the sugarand film-coating processes The advantages of lakes over soluble dyes, including the soluble natural colours, are multi-fold Advantages of lakes over dyes The following arguments apply not only to lakes as insoluble forms but to all other pigments, e.g iron oxides, titanium dioxide, etc During the sugar-coating process with soluble dyes specific dye concentrations are used in the applied coating syrups Very often this is performed sequentially with increasing dye concentration to achieve maximum colour The process must be carefully controlled to ensure that the finished tablets are not over-coloured or under-coloured However, if insoluble pigments are employed as colourants, especially when used in conjunction with an opacifier such as Page 59 titanium dioxide, a single colour concentration can be used, and since the colouring system is opaque, only one shade of colour will result In order to obtain a different shade, the ratio of pigment to titanium dioxide must be altered Thus, when employed in this manner, titanium dioxide serves both as an extender to reduce colourant costs and as an opacifier to yield only one shade of colour in a given situation The use of soluble dyes in coating solutions requires that the subcoated core must be perfectly smooth prior to the colouring stage This is essential in order to achieve a final uniform colour The presence of any surface irregularity before colour coating will result in an uneven colour, since it must be remembered that the final colour seen is an in-depth one resulting from light being reflected from the opaque underlayer of the subcoat Irregularities in the surface of this layer result in a variation in length of the path of reflected light, which manifests itself as a series of colour concentration differences, and hence an irregular colour (Fig 3.3) Common examples of this are shown in the case of poorly subcoated tablets where the sharp edge of the core has not been properly covered, resulting in a pale ring being visible around the edge of the tablet after colouring Since a pigment-coloured system is opaque, the resultant colour is not dependent on the depth (or thickness) of the colour layer, and the observed colour results from light which is reflected from the surface of the colour layer Provided that sufficient colour has been applied to cover the tablets uniformly, the resultant colour will be completely even (Fig 3.4) Fig 3.3 Shade irregularities with a dye-colour coat caused by uneven subcoat surface Page 60 Fig 3.4 Uniform shade obtained from pigment-coloured coat The typical dye-colouring process employs relatively low concentrations of colourants, and relies for its final colour on a substantially thick colour coat being applied This process takes time, with 30–50 colour applications being made If the process is rushed, and drying between each application is allowed to proceed too quickly, colour migration becomes a problem since there is a tendency for the soluble dye to ‘move’ with the moisture as it leaves the tablet This disrupts the uniformity of the colour layer, and results in an uneven final colour being achieved (Mattocks, 1958) Conversely, if the tablets are under-dried between each colour application, the final colour achieved might initially be uniform, but there is a tendency for the tablets to ‘sweat’ on storage, that is to say the excess moisture leaves the tablet and again causes migration of the colour resulting in final colour unevenness On the other hand, a typical pigment-colouring process employs a relatively high concentration of colour Since this is opaque and is not subject to colour migration problems, it can be applied and dried rapidly, resulting in an overall time-saving process without having a detrimental effect on the uniformity of the final colour The soluble dye-colouring system can pose a problem from a batchwise colour control point of view This is a transparent system, and if the number of colour applications varies from batch to batch either from carelessness, or desire to maintain a strict control over the final product weight, this will result in a variation in the thickness of the colour layer and, consequently, a batchwise variation in final colour Again it can only be stressed that as the pigment system is opaque, once complete colour coverage has been achieved, no variation in colour can occur Page 61 To summarize, a pigment system is superior to a water-soluble dye for colouring sugar-coated tablets due to: maintenance of evenness of colour because (a) the colour is not water soluble and thus is not prone to colour migration problems; (b) the colour is opaque, and thus is not affected by any minor unevenness in the subcoat layer; maintenance of colour uniformity from batch to batch, which results from the fact that, again because the colourant is opaque, the final colour is not affected by small fluctuations in the quantity of colour solution applied; reduction in overall processing time; reduction in the thickness of the colour-coating layer (see Anon., 1969) 3.4.5 Polishing After the colour-coating process the tablets have a somewhat dull, matt appearance which requires a separate polishing step to give them the high degree of gloss traditionally associated with sugar-coated tablets Methods vary considerably, but it is generally important that the tablets are dry prior to polishing Preferably they should be at least trayed overnight in a suitable atmosphere Some examples of polishing methods which are currently in use include: • Application of an organic solvent solution/suspension of waxes, e.g carnauba and beeswax A recently available variant on this theme provides an emulsion of both waxes in an aqueous continuous phase stabilized by a food and pharmaceutically acceptable surfactant The results obtained are equivalent to traditional methods utilizing organic solvent solutions but, of course, with the big bonus of aqueous processing • Use of wax-lined pan • Use of canvas-lined pan with wax solution/suspension • Finely powdered wax application • Mineral oil application In addition, there are polishing techniques reliant upon the use of glazes containing shellac in alcohol with or without waxes The use of these materials is rather more dependable, and is not so reliant on atmospheric conditions of temperature and humidity to obtain the optimum result This comment does not apply, however, to the aqueous material, which has a high degree of dependability in use 3.4.6 Printing Some regulatory authorities demand that tablets, be they coated or uncoated, should possess some detailed identifying mark Those authorities who not actually require this actively encourage it as part of the overall GMP and product acceptability requirements Unfortunately, unlike film-coated tablets, sugar-coated tablets cannot be monogrammed by engraving the punch tooling Instead a printing process is used Page 62 A typical edible pharmaceutical ink formulation is: shellac, alcohol, pigment, lecithin, antifoam and other organic solvents The printing process suitable for a formulation such as this is a modified offset gravure Shellac still has a traditionally dominant position as the lacquer most commonly encountered, but is slowly giving ground to cellulose derivatives in newer formulations as it can pose severe stability problems in some formulae Lecithin is frequently included to maximize the quantity of pigment that can be utilized Antifoam is a necessary ingredient to prevent the nuisance of foam build up in the ink container during a print run Careful formulation of solvent blends are necessary in order to achieve the correct drying time demanded by the particular application As in so many facets of coating in general, pharmaceutical ink formulation trends are to maximize the aqueous content of formulae The offset gravure process, while capable of producing impressive results, is sensitive to minor changes in procedure Attempts are being made to utilize more robust technology, for example ink-jet printing, in this process step 3.5 SUGAR-COATING FAULTS Because the sugar coating itself is deliberately isolated from the tablet core there is the possibility of much more standardization here than in the area of film-coating formulae, which are in intimate contact with the tablet surface and hence subject to faults arising from core-coating interactions A common fault is cracking and splitting of the sugar coat which is caused by excess residual moisture from the processing The remedy, of course, is to allow sufficient drying time between individual applications of syrup Reich & Gstirnir (1969), using a mercury porosimetry technique, have demonstrated that coating powders with high porosity lose moisture most easily during the coating process and showed the converse is also true for powders of low porosity, Wakimoto & Otsuka (1980) have developed a technique for measuring the distortion of a sugar coating which itself is a precurser to cracking Previous to this point, distortion had been difficult to measure The authors’ method utilized laser holographic interferometry and has the advantage that it is a non-invasive technique Inversion and stickiness are caused by the presence of inverted sugar which is difficult to dry adequately It can be encountered if slightly acidic colour-coating suspensions are maintained at too high a temperature for too long Sugar coatings are unfortunately brittle and are prone to chipping if subjected to an inappropriate mechanical stress The difficulties that can arise during the colour-coating step have been dealt with under the appropriate section Several problems can be encountered during the polishing stage One common fault is to attempt to polish tablets which are not quite smooth Under these conditions, wax will collect in the depressions on the tablet surface and remain as tiny white spots at the end of the process Page 63 3.6 DISSOLUTION AND STABILITY BEHAVIOUR Many authors have pointed out the crucial nature of the sealing step of the sugar-coating process and its ability to affect the disintegration and dissolution properties of the dosage form as a whole, for example Gross & Endicott (1960) Other authors have detailed instances of impaired dissolution characteristics of sugar-coated tablets and ascribed the behaviour to delayed break up of the sugar coating In a comprehensive study of fourteen batches of chlorpromazine sugar-coated tablets, Sawsan & Khalil (1984) reinforce this general point Other reports have suggested an incompatibility between the gelatin and calcium carbonate used in the subcoat (Barrett & Fell, 1975; Chapman et al., 1980) as a cause of impaired dissolution Sandell & Mellstrom (1975) report finding considerable variation in the disintegration time of batches of coated tablets, including sugar-coated tablets Romero et al (1988) have examined the stability of Ibuprofen coated tablets at elevated temperature and humidity storage They found the sugar-coated tablets to be especially sensitive to the storage conditions and suggest that this may be a general phenomena of the dosage form 3.7 INCORPORATION OF DRUGS IN THE SUGAR COATING This is a feasible practice with sugar-coated tablets and is usually performed for reasons of separating incompatible active substances Carstensen et al (1970), in a statistical study of the process, have deduced that tablet to tablet variation in drug content is inversely proportional to the number of coats applied to the tablets The larger the core the better the drug distribution will be compared to smaller core tablets REFERENCES Anon (1969) Drug Cosm Ind Aug , 63, 64, 144 Barrett, D & Fell, J.T (1975) J Pharm Sci 64, 335–337 Carstensen, J.T., Koff, A., Johnson, J.B & Rubin, S.H (1970) J Pharm Sci 59, 553–555 Chapman, S.R., Rubinstein, M.H., Duffey, T.D & Ireland, D.S (1980) J Pharm Pharmacol 32, 20P Gross, H.M & Endicott, C.J (1960) Drug Cosm Ind 86(2), 170, 171, 264, 288–291 Mattocks, A.M (1958) Am Pharm Mfg Assoc., Proc Prod Conf., 196 Reich, B & Gstirnir, F (1969) Cesk Farm 18, 112–113 Romero, A.J., Grady, L.T & Rhodes, C.T (1988) 14, 1549–1586 Sandell, E & Mellstrom, G (1975) Acta Pharm Suec 12, 293–296 Sawsan, A.E & Khalil, A.H (1984) Int J Pharm 18, 225–234 Seager, H., Rue, P.J., Burt, I., Ryder, J., Warrack, J.K & Gamlen, M.J (1985) Int J Pharm Tech Prod Mfr 6, 1–20  ... adding kg of coating powder to the remaining syrup before commencing the subcoating 3.4.3 Smoothing The product at the end of the subcoating will be too rough to continue with colour coating Smoothing... respect sugar coating differs from film coating as in this process each tablet passes through a zone of application which is subject to rapid and continuous drying 3.3 ADVANTAGES OF SUGAR COATING Despite... availability of raw materials make sugar coating an ideal coating method for developing countries • The process is generally not as critical as film coating; recovering and reworking procedures