Bos, Christine Elisabeth

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   University of GroningenTropical Tablets. The development of tablet formulations for use in tropical countries.Bos, Christine ElisabethIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1990Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Bos, C. E. (1990). Tropical Tablets. The development of tablet formulations for use in tropical countries.s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 08-06-2022nulatiort-SummaryTropical TabletsThe development of tablet formualtions for use in tropical countries.This Thesis deals with the development of tablet formulations for use in tropicalcountries. Many of the countries with a tropical climate are developing or Third Worldcountries. In Chapter I an introduction is given on the health care situation in generalin these countries and more specifically on the situation of the pharmaceutical care.These problems are related to the general problems in Third World countries such aslow income, undernourishment and low education level etc.In Chapter 1 a definition is given of the tropical climate. Also the influence of storageunder tropical conditions on the physical, microbiological and chemical stability ofdrugs in general and tablets in particular is described. For stability testing forworldwide marketing the world is divided into four climatic zones. For each zone theaverage kinetic temperature and the average relative humidity are defined. For the hotand dry climate and the hot and humid climate the storage conditions are 31"C and<65Vo relative humidity, respectively 31'C and > 65Vo relative humidity. The chemicalstability of drugs is influenced negatively by the high storage temperature of thetropical climate. In developing countries tablets may be dispensed just wrapped in apiece of paper or not packaged at all. Without protective packaging tablets may sorbwater during storage under tropical conditions, because tablets usually containhygroscopic excipients, such as disintegrants. The physical quali$ of tablets maydeteriorate due to this water sorption. The combination of high temperatures, theavailability of water and suitable substrates, such as starch and lactose, createsfavorable conditions for microorganisms to grow.In Chapter 2 the behaviour during compaction of corn, potato, rice and tapioca starchare compared. Rice starch proved to have better binding capacity than the three otherstarches. Moreover, rice starch is not susceptible to mixing with the lubricantmagnesium stearate. This in sharp contrast to potato starch that has no binding capacityafter mixing with magnesium stearate, due to the lubricant film formation. Thisdifference can be ascribed to the small particle size and the angular particle shape ofrice starch, s compared to potato starch, which has a round smooth particle shape.Due to this difference in particle size and shape, rice starch has poorer flow propertiesthan potato starch. After granulation of rice starch, a product is obtained with goodflow proprties and sufficient binding capacity after mixing with a lubricant. This productmay be used as a filler binder in the preparation of tablets by direct compression. Thefour investigated starches had sufficient water sorption capacity to serve as adisintegrant.In Chapter 3 further investigations on the properties of rice starch after granulation arepresented. Starch granulations were prepared with different techniques, in order toobtain granulations with different properties. The granule properties were analyzed inSummary 159:ion 2To- X ) V oVoToVo:ijo(oFrelation to the sensitivity of the granulations to mixing with a lubricant. A linearrelationship between the bulk density of the granulations and the lubricant sensitivitywas found. The flowability of the granulations proved to be the determining factor.Poor flow properties, which are characterized by low bulk densities, retard or impedethe formation of a lubricant film during mixing.In the first part of the Thesis the properties of native excipients, which may be usedas substitutes for the more commonly used products, were investigated. In the secondpart attention is paid to the stability of tablets. The relatively short consumers storagecondition in tropical countries is considered in relation to the physical andmicrobiological stability of tablets.In Chapter 4 the influence of storage under tropical conditions on the microbiologicalquality of tablets is investigated. The investigation of the microbiological quality of thestarting materials showed that rice and tapioca starch had a higher level of naturalcontamination than potato starch. All investigated starches met the requirements of theEuropean Pharmacopeia for microbiological quality of solid oral dosage forms. c-I-actose monohydratefpotato starch tablets, inoculated wtth Aspergillus niger sporesspoiled due to mould growth, when stored under extreme tropical conditions (31"C and95%o relative humidity). Under these conditions tablets prepared with o-lactose and riceor tapioca starch spoiled due to the growth of natural contaminants. No growth ofbacterial cells (Bacillus brevis) was observed during storage under these conditions.When the tablets were stored under more moderate conditions (31'C and757o relativehumidity) they were not at risk to microbiological spoilage. The addition ofpreservatives (sodium methylhydroxybenzoate or potassium sorbate) was evaluated withrespect to the efficacy against microbiological spoilage of tablets. A concentration oflVo w f w of either preservative prevented growth of.Asperyíllus níger on a-lactose/potatostarch tablets, stored at extreme tropical conditions. Addition of a presenative to a-lactose/potato starch tablets contaminated with Bacilhu brevk spores, did not affect theviability of these bacterial spores. The addition of preservatives to tablets prepared witha-lactose and rice or tapioca starch and stored under extreme tropical conditions,prevented microbiological spoilage caused by the growth of natural contaminants.In the Chapters 5 and 6 the influence of the tropical climate on the physical propertiesof tablets is investigated. In Chapter 5 a factorial design is used to describe theinfluence of four adjustable variables on physical tablet properties (crushing strengthand disintegration time) of c-lactose/rice starch tablets. The four adjustable variableswere: two process variables (compression force and starch concentration) and twostorage variables (temperature and relative humidity). Since the main parameter ofinterest is the decrease or increase in the physical tablet properties, the ratio of theparameters after storage to the initial parameters, was calculated for both the crushingstrength and the disintegration time and used as dependent variable. The use of theStorage to Initial Ratio (SIR) for the different tablet parameters wÍrs evaluated andcompared with the use of the absolute tablet parameters after storage. The Storageto Initial Ratio (SIlmeasure to express 'In Chapter 6 the St(least inÍluenced byformulations for trolfiller binder (o-lac1dihydrate) and a disior crospovidone). Aconcentration, storaproperties of the tabsuitable filler bindestarches and sodiundisintegrant.In the last three chause in tropical countltropical consumersselection of the excilnative excipients arepreparation of tableconsisting of only tuuse of the wet grasufficient binding abased on either theby direct compressirWith the proposedadded. All selectedIn Chapter 7 standarice or tapioca starcdrugs (mebendazoformulations resulteand microbiologicalIn Chapter 8 standzpreparation of tablmonohydrate, anhy,evaluated by adrhydrochlorthiazide,properties, both iniIn Chapter 9 modiJrice starch is a filproperties after midrugs (diazepam, ià(!EE:JU))ricant. A linearrricant sensitivitytermining factor,retard or impederich may be useded. In the secondonsumers storagehe physical andre microbiologicalfcal quality of the:r level of natural:quirements of thedosage forms. o-gtilut niger sporesnditions (31'C andr cJactose and rice.nts. No growth ofr these conditions.I and 75Vo relativeThe addition ofwas evaluated withA concentration ofrn c-lactose/potato, preservative to c-s, did not affect theblets prepared withropical conditions,rl contaminants.physical propertiesld to describe the(crushing strengthrdjustable variablesentration) and twomain parameter ofes, the ratio of therr both the crushingble. The use of thewas evaluated and)rage. The Storageto Initial Ratio (SIR) for the different tablet parameters proved to be a suitablemeasure to express the physical stability of the tablets.In Chapter 6 the Storage to Initial Ratio (SIR) is used to select excipients which areleast influenced by storage under tropical conditions and can be used in tabletformulations for tropical countries. Tablets were prepared from binary rnixtures of afiller binder (c-lactose monohydrate, anhydrous B-lactose or dicalciumphosphatedihydrate) and a disintegrant (corn, potato, rice, tapioca starch, sodium starch glycolateor crospovidone). A factorial design was used to study the influence of disintegrantconcentration, storage temperature and relative humidity on the physical tabletproperties of the tablets. a-I-actose monohydrate and anhydrous B-lactose proved to besuitable filler binders for use in tablet formulations for tropical countries. The fourstarches and sodium starch glycolate, in combination with a-lactose can be used as adisintegrant.In the last three chapters of this Thesis different tablet formulations are proposed foruse in tropical countries. The physical and microbiological stability during storage undertropical consumers conditions of the proposed formulations is considered. With theselection of the excipients, attention is paid to the price and the availability. If possible,native excipients are selected, other excipients are available worldwide. Generally thepreparation of tablets by direct compression is preferred, since it is a cheap method,consisting of only two process steps: mixing and compaction. However, sometimes theuse of the wet granulation technique is necassary, when the drug does not havesufficient binding andf or flow properties. The proposed standard formulations arebased on either the preparation of tablets by means of wet granulation (Chapter 7) orby direct compression (Chapters 8 and 9).With the proposed formulations tablets were prepared to which model drugs wereadded. All selected model drugs are on the List of Essential Drugs of the WHO.In Chapter 7 standard granulations are proposed based on a-lactose monohydrate andrice or tapioca starch. Both granulations were used to prepare tablets with trvo modeldrugs (mebendazol, an anthelmintic or diazepam, a psychotherapeutic). Bothformulations resulted in tablets with good initial tablet properties and sufficient physicaland microbiological quality after storage under tropical conditions.In Chapter I standard tablet formulations for direct compression are proposed for thepreparation of tablets by direct compression. The used filler binders were c-lactosemonohydrate, anhydrous B-lactose and modified rice starch. These formulations wereevaluated by adding two model drugs (diazepam, a psychotherapeutic orhydrochlorthiazide, a diuretic). Both formulations resulted in tablets with sufficientproperties, both initially as well as after storage under tropical conditions.In Chapter 9 modified rice starch is used as filler binder to prepare tablets. Modifiedrice starch is a filler binder with excellent flow properties and sufficient bindingproperties after mixing with a lubricant. Tablets weÍe prepared with several modeldrugs (diazepam, a psychotherapeutic, hydrochlorthiazide, a diuretic or isoniazid, aSummary 1616l(oFà(ItEEJatuberculostatic). The propertiesrequirements.In Chapter 10 tablet formulationswith a tropical climate.of the prepared tablets met the USP XXIare recommended. which can be used in countriesSamenvaTropen tablDe ontwikkelirIn dit proefschin de tropenzogenaamde o:inleiding gege\in het algemetzijn gerelateerkunnen hebbeIn hoofdstuk .beschreven wzfysische, microhet algemeenVoor de uitvorvier klimaatzoreen gemiddeltvastgelegd. Vozijn deze cond31"C en >659,De chemischetemperaturentabletten vaakZonder beschbewaren ondthygroscopischwateropnamecombinatie vaanwezigheidkunnen dieneonder tropiscIn hoofdstuktapioca-zetmhebben dangevoelig voortot aardappeheeft, tengetoegeschrevein vergelijkirdit verschil

Tropical Tablets. The development of tablet formulations for use in tropical countries.

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Tropical Tablets. The development of tablet formulations for use in tropical countries.

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