New Accelerating Stability Testing Protocol For O/W .
Research PaperNew Accelerating Stability Testing Protocol for O/WEmulsions Stabilized by Nonionic Surfactants IncludingStorage Temperature DeterminationA. K. HASSAN*57, Abdul Hakeem El-Refahy Street, Apartment 23, Nasr City, Cairo, EgyptHassan: New Accelerating Stability Testing Protocol for O/W CreamBetnovate , Daktacort , Daktarin , Hemoclar , Kenacomb and Lotriderm are O/W creams stabilizedby nonionic surfactant/s and distributed in the Egyptian market without stability problems. In this work,the above creams were used as stability reference standard creams to extrapolate numeral values for theproposed parameters of the new accelerated stability testing protocol. The temperature-conductivity relationsthat represent all the above tested creams have strong direct linear relationships. Determination coefficientR2 values of these relations were 0.909 and their yield values represented as temperatures were 2 . Thestability-indicating phase inversion temperatures of these creams were more than 80 . These commoncharacteristic results represent the basis parameters of the new accelerating stability testing protocol aswell as for the determination of the optimum storage temperature of the emulsion under examination. Theapplicability and validity of this protocol is confirmed by comparing the parameters results obtained fromnewly formulated O/W 2% miconazole nitrate cream to that obtained from the and also by subjecting allthe tested O/W creams including the newly formulated one to accelerating stability testing studies accordingto the recent approved Issues of ICH Guidelines Q1A (R2). These accelerating stability studies includethe measurements of the homogeneity, average weight and leakage test, drug content, pH, viscosity andmicrobiological analysis of the emulsion. Matching of the compared results and the approval of the stabilitytesting studies confirms the applicability and validity of the new protocol. The new protocol determinesthe optimum storage temperature condition required for each cream under examination through thedetermination of the yield value represented as temperature of its temperature-conductivity relation.Key words: New accelerating stability testing protocol, R2, Yield value represented as temperature, Stabilityindicating phase inversion temperature, Storage temperature determinationIn the recent times, there are many problems facingthe achieving and performing the accelerating stabilitytesting studies of pharmaceutical and cosmetic O/Wcreams as well as the determination of the optimumstorage temperatures. Tedious procedures, the cost andmost important is the time required for applying theaccelerating stability testing period which affect thedistribution of the drug in the market and consequentlythe patient seriously.The objective of this work is to reduce the cost greatlyand to save time by applying a new acceleratingstability testing protocol for evaluating the stabilityof O/W creams stabilized by nonionic surfactantsin addition to the determination of the optimumstorage temperature. Three main reasons pushing usfor applying and adopting the new protocol either inparallel with or instead of the current applied one inwhich the product is tested at temperature 40 2 andrelative humidity 75 5% for six months[1]. The first isthat, as with all accelerated test procedures, the primaryrequirement is that the stress applied should speed up,but not alter, the mechanism of deterioration operatingat ambient temperatures. The work of Enever, showedthat the viscous liquid crystalline phase that disappearsabove approximately 35 has a considerable stabilizinginfluence on the emulsions[2]. So it is of error andinappropriate to test any emulsion with accelerated testprocedure performed at 40 .The second is that, the protocol determines the optimumstorage temperature required for the stability of O/WThis is an open access article distributed under terms of the CreativeCommons Attribution-NonCommercial-ShareAlike 3.0 License, whichallows other the remix, tweak, and build up to the non-commercially, aslong as the author is credited and the new creations are licensed underthe identical terms.Revised 09 Jun 2016Received 10 Sep 2015*Address for correspondenceE-mail: kadry ibrahim173@yahoo.comMay - June 2016Accepted 17 Jun 2016Indian J Pharm Sci 2016;78(3):395-401Indian Journal of Pharmaceutical Sciences395
www.ijpsonline.comcream through the determination of the yield valuerepresented as temperature (YVT) of its temperatureconductivity relation as well as the temperatureto which the product will be cooled to obtain a finedispersion during the preparation process[3]. The thirdmain reason is that the new protocol takes only fewdays to judge stability.It is important to denote that the new acceleratingstability testing protocol is based on three mainfactors; the first one is that, the most stable O/Wemulsion is determined via the determination ofthe maximum R² value by applying of simple linearregression (least squares method) to the temperatureconductivity obtained data up to 80 [4]. This means thatthe temperature-conductivity relation of O/W creamunder investigation should have a strong direct linearrelationship. So it is very important to determine R² tojudge the stability.The second is the determination of the YVT. This willbe explained as the liquid and solid heterogeneousdispersions such as colloidal solutions, emulsions,liquid suspensions, ointments and similar products arefollowing the non-Newtonian equation of flow. Thenon-Newtonian plastic flow curves do not pass throughthe origin but rather intersect the shear stress axis (orwill if the straight part of the curve is extrapolatedto the axis) at a particular point referred to as theyield value. A Bingham body does not begin to flowuntil a shearing stress, corresponding to the yieldvalue is exceeded. At stresses below the yield value,the substance acts as an elastic material. In effect, aplastic system resembles a Newtonian system at shearstresses above the yield value[5]. It will be mentionedlater that the optimum storage temperature required forthe stability of the cream is equal to the YVT of itstemperature-conductivity relation, so it is important todetermine the YVT to judge the stability.Phase inversion temperature (PIT) represents the thirdmain factor affecting the stability of emulsions. It wasdiscussed in many researches. Shinoda and Saito,concluded that for satisfactory shelf life of emulsionsstabilized by nonionic surfactants, the PIT should be20-70 above the storage temperature. They concludedthat the instability of the emulsion is very sensitive tothe PIT, so that the selection of a suitable emulsifierby the PIT data is much more accurate and reliable,provided the temperature difference between thestorage temperature and the optimum PIT is knownwhich is covered in this work[3]. The emulsification at a396higher temperature especially near the PIT and coolingto storage temperature of the emulsion are effective inobtaining fine and uniform dispersions[3].Parkinson and Sherman concluded that, there isa general relationship between PIT and emulsionstability with the PIT increasing as the rate of globulecoalescence decrease. This suggests that it may bepossible to use PIT determinations as a simple andrapid method for evaluating emulsion stability[6]. Theparameters of the proposed new protocol were basedmainly on the above mentioned three factors.MATERIALS AND METHODSThe following instruments and reagents were used inthe study. RZR1 stirring paddle (Heidolph InstrumentsGmbh and Co. KG, Germany); A Jenway model4510 conductivity/TDS meter (UK); A Jenway model3510 pH meter (UK); Binder Incubators (Germany);Osworld Stability Chamber (India); Thermo scientificHPLC (USA); Brookfield Digital viscometer (USA);Thermometer 150 (76 mm 1 mm, N2 filled GH, Zeal,Ltd, England); glass-ware grade A (Ilmabor TGI,Germany); Burette (0.1/DIN/AS 50 ml, Germany;MS-H-Pro digital hotplate magnetic stirrer (USA);PGW153e 150.0 g, PGW253e 250.0 g, PGW453e,750.0 g, d 0.001 g ADAM balances (UK). Allequipment was calibrated, approved and ready for use.Stability reference standard creams (SRSCs):Betnovate , Daktacort , Daktarin , Hemoclar ,Kenacomb and Lotriderm O/W creams werepurchased from the Egyptian market. All these O/Wcreams were stabilized by nonionic surfactant/s asmentioned in their pamphlets and monographs. Theirnonionic surfactants are macrogol cetostearyl ether andcetostearyl alcohol, PEG and glycol stearate, macrogol6-32 stearate and glycol stearate, cetostearomacrogolnonionic, tween 60 and polyoxyethylene fatty alcoholether and cetosearyl alcohol, respectively.Stability of SRSCs and their approval:The stability of creams and consequently theirdistribution in the Egyptian market were approvedfrom three trusted/reliable organizations; the motherinternational companies, the companies in which thesecreams are manufactured under license in Egypt andthe Ministry of Health in Egypt. These creams weredistributed in the country of origin for 10 years beforetheir distribution in the Egyptian market accordingto the rules of the Ministry of Health in Egypt. TheyIndian Journal of Pharmaceutical SciencesMay - June 2016
www.ijpsonline.comwere manufactured in Egypt either in multinationalpharmaceutical companies or under the authority ofpharmaceutical companies in Egypt. The productsnames, their batch numbers, production dates,expiration dates, names of nonionic surfactants used,names of the mother international companies and thecompanies in which these creams are manufacturedunder license in Egypt were recorded in Table 1.inversion method. The water phase was heated to80 2 and added portion wise to the oily phasecontaining both emulsifiers at 80 2 within 30 s, whilestirring with RZR1 stirring paddle at speed of 664 rpm.Miconazole nitrate was added at 40 2, while stirringwith RZR1 stirring paddle at speed of 664 rpm. Theemulsion was mixed up to room temperature 25 2 [3,4].The emulsion was made in triplicate. All parameterswere measured after 24 h.Preparation of the tested SRSC samples:Yield value (YV), optimum storage temperature,conductivity and PIT range determination:150 g of each purchased O/W cream were weighedand stirred with RZR1 stirring paddle at speed of 664rpm for 5 min as a fixed time to assure a completemixing. Different emulsions were made in triplicate.All parameters were measured after 24 h.The cream under examination is sheared in the spacebetween the outer wall of a magnetic stirrer (rotating)and the inner wall of a beaker (stationary) into whichthe stirrer works. 60 ml of the tested cream wascontinuously agitated at 100 rpm with small propellerstirrer. The force shearing stress of the magneticstirring agitation and the rate of shear at 100 rpmspeed were fixed and allowed to reach equilibrium.The torque resulting from the viscous drag of thecream under examination was affected by increasingthe temperature at a steady rate up to 80 using MSH-Pro digital hotplate magnetic stirrer. The specificconductivity of each tested cream was measureddirectly, as it is, without dilution at room temperature25 2 , 40 , 50 , 60 , 70 and 80 . In this way, arheogram can be constructed by plotting temperatureversus conductivity by increasing temperature up to80 . In all of the tested cream samples, the temperaturewas displaced from the origin indicating that theemulsions exhibit a yield stress. The Bingham yieldPreparation of the newly formulated O/W 2%miconazole nitrate cream[4]:The following chemicals were used in formulation,miconazole nitrate (Jiangsu Nhwa PharmaceuticalCo. Ltd. China), paraffin oil (Apar Industries Co. Ltd.India), soft paraffin (Jell Pharmaceuticals Pvt Co. Ltd.India) and beeswax (Cisme Co. Italy), Tween 80 andSpan 80 (Kolb Co. Switzerland), propyl paraben base(Salycylates and Chemicals Co. Ltd. India) and methylparaben base (Wuhu Huahai Biology Engineering Co.Ltd. China), sorbitol (Roquette Lestrem Co. France) andwater for injection (Grand Pharma for PharmaceuticalIndustries Co. Egypt). Emulsion composition wasrecorded in Table 2.The emulsions were prepared by the sudden phaseTABLE 1: DATA OF THE PURCHASED O/W CREAMS.Product nameBetnovate creamBatchnumberN100797Daktacort creamProd. Date Exp. Date Nonionic n creamDBE0526Feb-13Jan-15Hemoclar cream3EG094Jun-13May-16Kenacomb creamN101485May-13May-15Lotriderm cream130239Jan-13Jan-161Jun-14Jun-16Miconazole nitratecreamMother Company/Manufactured byMacrogol cetostearylGlaxoWellcome, UK/ether/cetostearyl alcohol GlaxoSmithKline, S.A.E., EgyptPEG and glycol stearateJanssen Pharmaceutica, Belgium/Minapharm, EgyptMacrogol 6-32 stearate and Janssen Pharmaceutica, Belgium/glycol stearateMinapharm Egypt.CetostearomacrogolSanofi-Aventis, France/nonionicSanofi-Aventis, S.A.E., EgyptTween 60 (PolysorbateGlaxoSmithKline, UK/60)/polyoxyethylene fatty Smithkline, Beecham, Egyptalcohol etherCetosearyl alcoholSchering Plough Corporation,USA/Medical UnionPharmaceutical, EgyptTween 80 / span 80Grand Pharma, EgyptThe products names, their batch numbers, production dates, expiration dates, names of nonionic surfactant/s, the mother companies ofthese creams and the companies in which these creams are manufactured under license in Egypt. All the products are O/W creamsMay - June 2016Indian Journal of Pharmaceutical Sciences397
www.ijpsonline.comTABLE 2: COMPOSITION OF THE NEWLYFORMULATED O/W 2% MICONAZOLE NITRATECREAM.Gm/100 gm2.017.012.05.03.53.50.025.00.1551.83The composition of the newly formulated O/W 2% miconazolenitrate cream (9.236 And 9.65 are HLB values of the system andthat of the surfactants blend respectively).stresses for all the samples can hence be obtained fromthe least squares fitted lines by extrapolating the linearlines to the zero temperature X-axis[7].As known, the material does not begin to flow untila shearing stress, corresponding to the yield value isexceeded. In the present work, YVT and consequentlythe material does not begin to flow until a shearingstress accompanied with temperature, correspondingto the yield value is exceeded. Since the flow of thematerial will affect its stability, so for good stabilitythe tested cream should be stored (if possible)in a temperature equals to the yield value whichrepresented as temperature. Accordingly the optimumstorage temperature should be equal to the YVT whichrepresents a new approach indicating the importanceof the yield value as factor affecting studying ofemulsions stability. The points of intersection of theyield values may revealed using figure 1 and can beobtained when needed from the least squares fitted linesby extrapolating the linear lines to the zero temperatureX-axis[7].PIT range was detected as a fall of the specificconductivity between any two successive temperaturevalues or they may be detected when two successiveconductivity values are nearly equal (steady state ofconductivity values). The results quoted are the meansof three determinations[4].Accelerating stability testing for all tested creams:Stability studies were carried out to the purchasedO/W SRSCs as well as to the newly formulated O/W2% miconazole nitrate topical cream according to therecent approved Issues of ICH Guidelines Q1A (R2),in which the product is tested at temperature 40 2 3982000Conductivity (uS/cm)Emulsion compositionMiconazole nitrateLiquid paraffinSoft paraffinBees waxTween 80Span 80Propyl parabenSorbitolMethyl parabenWater for re (o)Fig. 1: Relation between the temperatures vs. conductivities upto 80 for all O/W tested creams.In all of the tested cream samples, the conductivity as a functionof the temperature was displaced from the origin indicatingthat the emulsions exhibit a yield stress. The Bingham yieldstresses for all the samples can hence be obtained from theleast squares fitted lines by extrapolating the linear lines tothe zero temperature X-axis. Betnovate, y 35.96x-1031,R2 0.914; Daktacort, y 6.859x-149.3, R2 0.944; Daktarin,y 8.979x-227.0, R2 0.942; Heamoclar, y 25.96x-829.8,R2 0.909; җ Kenacomb, y 34.09x-712.7, R2 0.983; Lotriderm,y 28.70x-711.2, R2 0.954; Miconazol, y 10.59x-229.0,R2 0.935.and relative humidity 75 5% for six months[1]. Theseaccelerating stability studies include the measurementsof the homogeneity, average weight and leakagetest, drug content in the emulsion (identification andassay of the active constituents), pH, viscosity andmicrobiological analysis of the emulsion. Thesemeasurements were performed in addition to thetemperature-conductivity relations that represent allthe above tested creams. The results obtained from thestability studies indicate that all the tested O/W creamsattained their physical, chemical and microbiologicalattributes and no significant change occurred duringthe study period.RESULTS AND DISCUSSIONThe conductivities of each O/W emulsion set ofthe purchased O/W SRSCs were measured at roomtemperature 25 2 , 40 , 50 , 60 , 70 , 80 and a relationbetween the temperature vs. conductivity up to 80 wasplotted by applying the simple linear regression (leastsquares method) statistical analysis[4]. Temperatures andaverage of responses of conductivities were recordedin Table 3. Temperature-conductivity measured valueswere used in the application of the statistical analysis, therheological measurements as well as the determinationof the stability-indicating phase inversion temperatures(SIPIT) range measurements.Indian Journal of Pharmaceutical SciencesMay - June 2016
www.ijpsonline.comTABLE 3: AVERAGE RESPONSES OF CONDUCTIVITIES.Temperature25º nazole108.3160218394525663Average responses of conductivities in µS/cm at 25 2, 40,50 ,60, 70 and 80º for each O/W tested creams including the newly formulatedO/W 2% miconazole nitrate cream.The least squares regression line equation calculatesthe slope b (the change in Y for unit change in X), theintercept a (the predicted value of Y when X 0) and R²(known as the coefficient of determination). As knownthat, in the case of models with an intercept, R² canbe interpreted as the proportion of the variation in Ythat is accounted for by the predictor variable X afteradjusting Y by its mean. It runs from 0 to 1, with 1indicating perfect prediction of Y from X[4,8].In all of the tested cream samples, the conductivityas a function of the temperature was displaced fromthe origin indicating that the emulsions exhibit a yieldstress. The Bingham yield stresses (represented astemperatures YVTs) for all the samples can hence bedetermined/obtained from the least squares fitted linesby extrapolating the linear lines to the zero temperatureX-axis. The points of intersection of the yield valuesmay revealed using figure 1 and can be obtainedwhen needed from the least squares fitted lines byextrapolating the linear lines to the zero temperatureX-axis[7]. Absence of phase separation, as well as, theabsence of the abrupt change in conductivity up onheating up to 80 indicates that the SIPITs of all thetested cream samples are more than 80 .The results of the statistical analysis, YVT and theSIPIT determination indicated that all the testedcreams have common characteristic parameters. Theseparameters represent the basis of the new acceleratingtesting protocol required for evaluating the stability ofthe O/W emulsions stabilized by nonionic surfactant/s,that is to say, the temperature–conductivity relationsthat represent all the tested creams have strong directlinear relationships. R2 values of these relations were 0.909 and their YVTs were 21 , in addition to, theSIPITs of these creams were more than 80 .As mentioned before, since the optimum storagetemperature is actually equal to the YVT, so forgood stability the tested cream should be stored ina temperature equals to the YVT of its relation. Forthat, the optimum storage temperatures required forMay - June 2016the stability of Betnovate , Daktacort , Daktarin ,Hemoclar , Kenacomb and Lotriderm O/W creamsare in the range of (24-28 ), (20-24 ), (24-28 ), 32 ,(20-24 ) and (24-28 ), respectively. This represents anew approach indicating the importance of the yieldvalue as factor affecting studying of the emulsionsstability and consequently the suitability of the linearregression analysis-Bingham model as a statisticalmethod of analysis of the obtained data was discussedin previous paper[4]. Data were revealed in fig. 1. R²,YVT and PIT results were obtained from fig. 1 andwere recorded in Table 4.The applicability and validity of the new proposedprotocol was confirmed by matching the parametersresults obtained from the newly formulated O/W2% miconazole nitrate cream with that obtainedfrom the above mentioned purchased SRSCs. It wasconfirmed also by subjecting all the tested O/W creamsincluding the newly formulated one to acceleratingstability testing studies. These studies were carriedout according to the recent approved Issues of ICHGuidelines Q1A (R2), in which the product is testedat temperature 40 2 and relative humidity 75 5%for six months. These accelerating stability studiesinclude the measurements of the homogeneity, averageweight and leakage test, drug content in the emulsion(identification and assay of the active constituents), pH,viscosity and microbiological analysis of the emulsion.These measurements were performed in addition tothe temperature-conductivity relations that representall the above tested creams. Temperatures and averageof responses of conductivities of the newly formulated2% miconazole nitrate cream were recorded in Table 3.The results of the statistical analysis, YVT and theSIPIT determination indicated that the relation ofthe newly formulated O/W 2% miconazole nitratecream has strong direct linear relationship betweentemperature and conductivity. R2 value of this relationis 0.935. YVT of the relation is more than 21 andthe SIPIT of this cream is more than 80 . The resultsIndian Journal of Pharmaceutical Sciences399
www.ijpsonline.comobtained from the stability studies indicate that thetested O/W miconazole nitrate cream attained itsphysical, chemical and microbiological attributes andno significant change occurred during the study period.Matching of the compared results and the approval ofthe stability testing studies confirms the applicabilityand validity of the new protocol. Since the optimumstorage temperature is actually equal to the YVT, sothe optimum storage temperatures required for thestability of the newly formulated cream is mainly 22 (20-24 ). Data were revealed in fig. 1. R², YVT andSIPIT Results were obtained from fig. 1 and wererecorded in Table 4.determines the optimum storage temperature of thecream under examination/investigation through thedetermination of the YVT which accordingly enablesus and the manufacturing companies to designate theoptimum storage temperature required for the stabilityof that cream at different climates zones as well as thetemperature to which the product will be cooled to obtaina fine dispersion during the preparation process of theproduction batch. Shinoda and Saito concluded that,the emulsification at a higher temperature especiallynear the PIT and cooling to storage temperature of theemulsion are effective in obtaining fine and uniformdispersions[3].The new protocol determines the optimum storagetemperature condition required for each cream underexamination through the determination of the YVT ofits temperature-conductivity relation which representsa new approach indicating the importance of the yieldvalue as factor affecting studying of the emulsionsstability and consequently the suitability of the linearregression analysis-Bingham model[4] as a statisticalmethod of the analysis of the temperature-conductivityobtained data.The new protocol provides us an alternative acceleratedtest procedure as the current applied one is performed at40 and this temperature will alter rather than speed upthe mechanism of deterioration operating at the ambienttemperatures. This temperature is not acceptable andinappropriate because the viscous liquid crystallinephase that disappears above approximately 35 has aconsiderable stabilizing influence on the emulsions.The present work proves the applicability and validityof adopting a new accelerating stability testing protocolfor evaluating the accelerated stability of the O/Wemulsions stabilized by nonionic surfactant/s. It maybe applied either accompanied with or instead of thecurrent applied protocol of the recent approved Issuesof ICH Guidelines Q1A (R2).Criteria of the new protocol provided that, thetemperature-conductivity relation of O/W creamunder investigation should have strong direct linearrelationship. R2 value of this relation should be 0.909and its YVT should be 21 , in addition to, the SIPIT ofthis cream should be more than 80 . The new protocolTABLE 4: RESULTS OF ALL THE TESTED O/WCREAMS.SRSCs and newlyformulated miconazolecreamBetnovate creamDaktacort creamDaktarin creamHeamoclar creamKenacomb creamLotriderm creamMiconazole nitrate creamR² 28-32º20-24º24-28º32.0º20-24º24-28º20-24º 80º 80º 80º 80º 80º 80º 80ºSRSC: Stability reference standard creams), YVT: Yield valuesrepresented as temperatures and SIPIT: Stability-indicating phaseinversion temperatures400The new protocol takes only few days to judge thestability, so it reduces cost greatly and save time thataffect the distribution of the drug in the market andconsequently the patient seriously.Acknowlegments:The author thanks Grand Pharma for PharmaceuticalIndustries Company, Egypt.Financial support and sponsorship:Nil.Conflicts of interest:There are no conflicts of interest.REFERENCES1.2.3.4.Stability testing of new drug substances and productsQ1A (R2). International Conference on Harmonization ofTechnical Requirements for Registration Of PharmaceuticalsFor Human Use. 2003.Enever RP. Correlation of phase inversion temperature withkinetics of globule coalescence for emulsions stabilized bypolyoxyethylene alkyl ether. J Pharm Sci 1976;65:517-20.Shinoda K, Saito H. The stability of O/W type emulsions asfunctions of temperature and the HLB of emulsifiers: Theemulsification by PIT-method. J Colloid Sci 1969;30:258-63.Hassan AK. Effective surfactants blend concentrationdetermination for O/W emulsion stabilization by two nonionicsurfactants by simple linear regression. Indian J Pharm Sci2015;77:461-9.Indian Journal of Pharmaceutical SciencesMay - June 2016
www.ijpsonline.com5.6.Sinko PJ, Singh Y, editors. Martin’s Physical pharmacy andpharmaceutical sciences. Baltimore: Lippincott Williams andWilkins, Wolters Kluwer business; 2011.Parkinson CJ, Sberman P. Phase inversion temperature asan accelerated method for evaluating emulsion stability. JColloid Interface Sci 1972; 41:328-30.May - June 20167.8.Rashaida AA. Flow of a non-Newtonian Bingham plastic fluidover a rotating disk. Saskatchewan: Department of MechanicalEngineering, University of Saskatchewan; 2005.Chatterjee S, Hadi AS. Regression Analysis by Example. 4thed. New Jersey: John Wiley and Sons Inc; 2006.Indian Journal of Pharmaceutical Sciences401
80 2 and added portion wise to the oily phase containing both emulsifiers at 80 2 within 30 s, while stirring with RZR1 stirring paddle at speed of 664 rpm. Miconazole nitrate was added at 40 2, while stirring with RZR1 stirring paddle at speed of 664 rpm. T
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