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EXCIPIENTS-solid Dosageform-Handbook of Pharmaceutical Manufacturing Formulation-2ed-6 Volume

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  Guidance on Formulating Compressed Solids  67  There are a few products, such as some of the antihis-taminetablets,inwhichthedrugsubstanceisappliedduringthe coating process. Other products require the active drugsubstance to be applied as a dust on tacky tablets as partof the coating process. For these products, it is particularlyimportant to apply the drug in the coating solution in manycontrolled applications.Again, it is important as part of the validation of theseprocesses to demonstrate dose uniformity and dissolutionand control the parameters of the coating process.  XVIII. EXCIPIENTS Excipients are well defined in the official pharmacopoeia.No specific pharmaceutical grades are specified in this book,except where there is a specific reason to do so. How-ever, it is known that different pharmacopoeia may havedifferent specifications, such as particle size, impurities,moisture, etc. The harmonization of excipients, a global ef-fort that is underway, would go a long way in makingthe choice of excipients. The manufacturer is referred tohttp://www.ipecamericas.org/index.html and the  Handbook of Pharmaceutical Excipients  for further advice. A large num- ber of proprietary excipients are widely used, such as Ac-Di-Sol  R  , Explotab  R  , Aerosil  R  , Ludipress  R  , Avicel  R  , etc.,and many of these are now part of pharmacopoeias. Thereis a significant advantage, though the cost is high, in usingthese ingredients because they offer additional benefits, of-ten reducing processing time. Additionally, the suppliers of these ingredients are always willing to provide formulationsupport and have large databases, particularly pertaining tostability of drugs, that may be of great value to manufac-turers. The following sections (A–F) list the most commonlyused excipients in compressed solids.  A. Coating Agent Carboxymethylcellulose, sodium cellacefate (formerly cel-lulose acetate phthalate), cellulose acetate, cellulose ac-etatephthalate(seecellacefate),ethylcellulose,ethylcelluloseaqueous dispersion gelatin glaze, pharmaceutical hydroxy-propyl, cellulose hydroxypropyl methylcellulose, hydroxy-propyl methylcellulose phthalate (see hypromellose ph-thalate), hypromellose phthalate (formerly hydroxypropylmethylcellulose phthalate), methacrylic acid copolymer,methacrylicacidcopolymerdispersion,methylcellulosePEG,polyvinylacetate,phthalateshellacsucrose,titaniumdioxidewax, carnauba wax, microcrystalline zein. B. Glidant Calcium silicate, magnesium silicate, silicon dioxide, col-loidal talc. C. Tablet Binder  Acacia alginic acid carboxymethylcellulose, sodium cellu-lose, microcrystalline dextrin ethylcellulose gelatin glucose,liquid guar gum hydroxypropyl methylcellulose, methylcel-lulose polyethylene oxide povidone starch, pregelatinizedsyrup. D. Diluent Calciumcarbonate,calciumphosphate,dibasiccalciumphos-phate, tribasic calcium sulfate cellulose, microcrystallinecellulose, powdered dextrates, dextrin, dextrose, excipient,fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch,pregelatinized sucrose, sugar, compressible sugar, confec-tioner’s sugar. E. Disintegrant Alginic acid cellulose, microcrystalline croscarmellosesodium, crospovidone polacrilin, potassium, sodium starch,glycolate starch, starch, pregelatinized. F. Lubricant Calcium stearate, glyceryl behenate, magnesium stearate,mineral oil, light PEG, sodium stearyl fumarate stearic acid,stearic acid, purified talc, vegetable oil, hydrogenated type Izinc stearate.Thechoiceofexcipientsismadebasedonthreedistinctconsiderations:     Compatability with the active drug—Many excipientshave active functional groups that can interact with theactive drug and enhance its degradation. Even the waterof hydration or moisture in the excipients can create diffi-cultiesinsolid-statedegradationoftheactivedrug;so,itisnot only the selection of the ingredient but also the grade(such as anhydrous or hydrous) that is important.     Effect on efficacy—Excipients are known to alter the re-lease patterns (e.g., a strong binder would delay break upofthetablet)andoftenbindthedrugmoleculesinthegas-trointestinal tract. The evaluation should be made in thefullcompositionofingredientsbecausethepresenceoftwoingredients may change their individual characteristics.     Cost of formulation—Even though excipients contribute asmall cost of the total formulation, the declining cost of APIs makes the selection of excipients based on cost animportant consideration. This is particularly true whengeneric manufacturers are filing ANDAs knowing wellthat they will compete on a price basis. However, the to-tal cost of formulation should not only be calculated onthe basis of excipients. Often, the use of expensive ex-cipients reduces process time, eliminates certain processsteps, and even allows for the use of a cheaper packag-ing material. The manufacturer must, therefore, calculatethe overall manufacturing cost. This aspect of formulationcreates unique considerations by the multinational com-panies doing business worldwide; they are often forced todevelopalternateformulationsdependingontheavailabil-ity of excipients, manpower cost, and local environmentalconsiderations.The rule of thumb in the selection of excipientsremains—keep it simple and at the bare minimum. The goalof excipients selection should be clearly defined—the dosageform yielding to a solution form at a predetermined rate (notnecessarily the fastest in all instances).The formulations described in this volume provide aquantitative listing of excipients recommended. An astuteformulatorwouldknowtheneedtoaltertheirquantitybasedonthetypeofequipmentusedtoprocessthem,thesizeofthe batch processed at one time, and the quality of compressedproductobtained.Therefore,allquantitativelistingsofexcip-ients must be considered the best starting point, which can be adjusted and optimized, if necessary. In many instances, arange of excipients is allowed, such as in the case of a bindersolution, to yield a suitable mass (as it is often described inthe formulation of wet massing).Where exact quantities of excipients are not available, but the excipients are identified for an innovator’s prod-uct, this is still a better starting point than establishingthe choice of excipients. Knowledge of the physicochemical  68   Handbook of Pharmaceutical Manufacturing Formulations: Compressed Solid Products characteristics of the API takes a more pivotal role when theinformation available is limited. Obviously, one can readilyidentify the role of the identified, but not quantified, excip-ients. Some experimentation is required. However, as pro-vided throughout this volume, significant knowledge can be gained by benchmarking the formulation. Other similardrugs or excipients should provide a good clue of the start-ingquantities.Itisnoteworthythatinobtainingthecopiesof competitor NDAs, through the Freedom of Information Act,some quantities are often redacted, leaving the formulator toguess. However, this should not be a difficult step, as long asthe quantities of excipients chosen provide a similar weight,thickness, and disintegration and dissolution characteristics.A common practice by innovator companies, as theNCEgetsclosertothepatenttermexpiry,istopatentavarietyofformulations;forexample,inthecaseofAug-mentin  R  ,theinnovator chose to patent a different combination of amoxi-cillin and clavulanic acid and developed a composition forpediatric therapy. The purpose of this exercise is to keepgeneric competition out; the generic product in some casesmay be the same, but not exact. The patent-end changes mayalso include changes in specification, choice of solvent sys-tems used, or other cosmetic changes. However, a genericmanufacturer would do well by just following the srcinalformulation (for obvious reasons of regulatory compliance) because this has withstood the test of time. The author rec-ommends that no changes should be made to an otherwiseworking formula, albeit this may improve processing, untilsuch a time that the generic manufacturer has sufficient ex-perience with the product. Most unusual things can happenwhenunsuspectingchanges,appearingbenignatthesurface,are made to proven formulas. Given the cost of bioequiva-lence study requirements for compressed solids, changes informulation should not be made unless essential and, eventhen, only for compliance purposes.  XIX. DIRECT COMPRESSION Thetechnologyinvolvedindirectcompressionassumesgreatimportance in the tablet formulations, because it is often thecheapest means, particularly in the production of generics,that the active substance permits. The limiting factors are thephysical properties of the active substance and its concen-tration in the tablets. Even substances such as ascorbic acidthat are hardly suitable for direct compression, owing to thefriability of their crystals, can normally be directly pressedinto tablets at concentrations of 30% to 40%. However, thistechnique is not as suitable if the content of ascorbic acid ishigher. This limit may be shifted upward by special directcompression auxiliaries, for example Ludipress. Two impor-tant alternatives, viz. Ludipress grades and Kollidon VA 64,can be found in the BASF line of pharmaceutical excipientsfor direct compression.Ludipressisaspecialityderivedfromlactose,Kollidon30,andKollidonCL.Itthuscombinesthepropertiesofafiller, binder, disintegrant, and flow agent and also often acts as arelease accelerator. By virtue of its versatility, formulationscontainingitareusuallyverysimple.Itcanalsobecombinedwith almost all active substances with the exception of thosethat enter into a chemical interaction with lactose (Maillardreaction).Active substances, for example many analgetics, be-have very differently with Ludipress when the dosage isextremely high. Acetylsalicylic acid and metamizole can bepressed when little Ludipress has been added; ibuprofen re-quiresalargeramount;andthefractionofLudipressrequiredinthetabletsistoolargeforparacetamol( = acetaminophen).An alternative to the Ludipress grades is the outstand-ing dry binder Kollidon VA 64 together with excipients, forexample calcium phosphate, microcrystalline cellulose, lac-tose, or starch, and a disintegrant, for example Kollidon CL.This combination even allows 500 mg of paracetamol to bepressed into good tablets with a weight of 700 mg.Nootherdrybinderhasabindingpowerandplasticitycomparable to those of Kollidon VA 64. Plasticity, in partic-ular, is an important parameter in direct compression. Thisproperty of Kollidon VA 64 is not adversely effected by in-creasing the pressure. The beneficial properties of KollidonVA64canalsobeexploitedfortheproductionofconcentratedactive substance that is subsequently used for direct tablet-ting. Kollidon VA 64 and Ludipress can also be combinedwith one another.  XX. FILL WEIGHTS Fill weights are provided in all formulations. These may notcoincidewithscaleformanyreasons,asdescribedelsewhere:differences in the salt forms, hydrates, or overages addedin manufacturing and also to provide the extra margin of variation in filling during fast compression operations.  XXI. FINAL PACKAGING A formulation design does not end with assuring that goodtablets are formed; it must allow for handling during pack-aging, such as sliding into blister sheets or dropping into bottles. Actual fill runs must be conducted, and then the fin-ished product must be subjected to simulated, and finally,the actual rigors of shipping before finalizing a formulation.Know that during shipping, the product may be exposed todiverseandoftenharshweatherconditions.Silicagelisoftenplaced in the finished packs, or cotton is inserted, mainly toprovide moisture or absorb odor (in the case of cotton).  XXII. FINAL TESTING Finished product testing, particularly assay, content unifor-mity, and dissolution, is required. In the review of dissolu-tion test results, it is important to eventually see results closeto 100% dissolution. In some cases, manufacturers profilethe dissolution results only to the specification. However, if lower but still acceptable results are obtained (such as 85%),it is important to continue the test. This can be performed by increasing the speed of the apparatus. If a product com-pletely dissolves, yet only results in a value of 85%, it mayindicate some problem with the test. Likewise, high dissolu-tion results (115%) also indicate some problem with the test.Obviously,unusualoratypicalresultsshouldbeexplainedinthe validation report.  XXIII. FINES Solids,whengrindedtosmallparticlesizes(aswhenpassingthrough sieves or crushing granules), yield a distribution of variousparticlesizes.Acertainamountofveryfineparticles,

Imperial Knight

Jul 23, 2017
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