Stability of Powder-Filled Hard Gelatin Capsules Stored ... - Capsugel

Stability of Powder-Filled Hard GelatinCapsules Stored in Standard I.C.H. ConditionsT3086S. Robin, E. Groshens, J. Cuevas and D. CadéChemical R&D Department, CapsugelPoster presented at the 2010 Annual Meeting and Exposition of the AmericanAssociation of Pharmaceutical Scientists.New Orleans LouisianaNovember 14-18, 2010

PURPOSEThe work presented hereafter illustrates thatthe selection of the blister type is crucial todocument the stability of product filled inhard gelatin capsules when tested under thestandard I.C.H. conditions.Table 1: Porosity of various blister is depending on their composition.Aluminum/Aluminum is our reference with almost “zero” water transmission.The purpose of this study is to determine the designspace for gelatin hard capsules filled withacetaminophen tablets in blisters of variableporosity and stored under I.C.H. [1] storageconditions.Photo 1: Capsugel Coni-Snap®capsules.Coni-Snap® hard gelatin capsule (Photo 1)is proposed in different sizes, colors, andfrom different gelatin origins (porcine,bovine, fish) since more than 50 years toencapsulate powders, pellets, tablets andother solid-like products.With the expansion of the variety ofproducts filled into hard gelatin capsules, thestability studies are more and moreimportant. We decided to focus on blister(Photo 2).Photo 2: Examples of blister.METHODProduct descriptionThe capsules studied are Coni-Snap® hard gelatincapsules size#0 white opaque, filled with 500mgacetaminophen tablets.Testing protocolCapsules were packed in blister with variableporosity (Table 1) and in moisture-tight aluminumblister to compare the effect of packaging. Theblisters were stored under I.C.H. conditions, namely25°C.60%RH, 30°C.65%RH, 30°C.75%RH and40°C.75%RH and analyzed after 1 month and 3months.Measurements performedDuring the stability study, capsules arecharacterized by:• Dimensions: 10 capsules are visuallyinspected and their closed length measured.Specification is 21.7mm (+/-0.3).• Dissolution profile[2]: 6 capsules aresubmitted to USP dissolution method forAcetaminophen capsules (Apparatus IIpaddle, 50 rpm, demi water at 37°C).2/4Stability of Powder-Filled Hard Gelatin Capsules Stored in Standard I.C.H. Conditions- AAPS 2010- T3086

Tolerances—Not less than 75% (Q) of thelabeled amount of Acetaminophen isdissolved in 45 minutes.• Gelatin semi-crystalline structure[3]:3 capsules are cut in small pieces and10mg randomly analyzed usingdifferential scanning calorimetry(Mettler Toledo, DCS1 StareSystem) Result of interest here is themelting enthalpy expressed in mJ/gof product equilibrated at 50%RH.• Water content: water content isevaluated from glass transitiontemperature from calibration curvedone with LOD Method (105°C for18h).blisters (PVC, PVC/PVdCs) stored at 40°C/75%RH(Table 2).Table 2: Closed length of capsules after storage in ICH conditionsCapsule dissolution: dissolution profile of capsulesfilled with APAP and stored in all I.C.H. conditionsremain stable for 3 months, except the capsulesstored in PVC and PVC/PVdCs blister inaccelerated conditions 40°C/75%RH (Table 3).RESULTSStorageBlisterPVCPVC/PVdC(250/40)PVC/PVdC(250/90)PVC/PE/PVdCPVC/PVdC/PVCPVC/Aclar/PVCPVC/Aclar/PVCPVC/Aclar/PVdCAlu / AluCapsule water content: The overall resultsare consistent with expectations (Fig.1& 2):water content remains stable in blistersexcept at 40°C and 75%RH, where itincreases significantly in porous blisterssuch as PVC and PVC/PVdCs.Water content (%)17161514131211101 month 3 monthsFig. 1: Evolution of water content in capsules after storage in acceleratedcondition 40°C.75%RH for 1 and 3 months. For information, Initial watercontent in capsules is 14.2%.Capsule dimension: the length of closedcapsules after storage remains withinspecifications (21.7mm+/-0.3) whatever theblister porosity, except the case of porousPVCPVC/PVdC40PVC/PVdC90PVC/PE/PVdCPVC/PVdC/PVCPVC/Aclar51/PVCPVC/Aclar76/PVCPVC/Aclar/PVdCAlu/Alu25°C - 60%RH PASS not tested PASS not tested not tested not tested not tested PASS not tested30°C - 65%RH FAIL not tested PASS not tested not tested not tested not tested PASS not tested30°C - 75%RH FAIL PASS PASS PASS PASS PASS PASS PASS PASS40°C - 75%RH FAIL FAIL FAIL FAIL PASS PASS PASS PASS PASSTable 3: Dissolution results versus blister & ICH conditionsWe documented in Fig.2 that capsules are stable inaccelerated conditions, even in open conditions;blisters containing PVC induced in our study gelatincross-linking in hot and humid conditions.% Acetaminophen dissolved110.0100.090.080.070.060.050.040.030.020.010.00.00 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75Time in minFilled HGC in PVC blister - 1M 40°C - 75%RHFilled HGC in OPEN box - 1M 40°C - 75%RHEmpty HGC in open box - 1M 40°C - 75%RHFilled & empty HGC - T = 0Fig.2: Example of dissolution profile of HGC capsules stored at40°C/75%RH for 1 month: (∇) filled and stored in PVC blisters, (▲)filled and stored in open bottle, (♦) empty and stored in open bottle, (●)reference before storage3/4Stability of Powder-Filled Hard Gelatin Capsules Stored in Standard I.C.H. Conditions- AAPS 2010- T3086

Gelatin structure in capsule: After 3months storage, gelatin structure doesnot change. In accordance with abovewater content results, glass transitiondecreases in gelatin stored in porousblisters (PVC, PVC/PVdCs) andaccelerated conditions.Fig. 3: Gelatin structure after 3 months storage: meltingtemperature (above), glass transition temperature (middle) andmelting enthalpy (bottom).CONCLUSIONSWe demonstrated that hard gelatin capsulesare stable in all I.C.H. conditions providedthat blisters are adequately selected: capsuledimensions, gelatin water content andstructure and dissolution profile arepreserved after 3 months.We detected anomalies in porous blisterssuch as PVC and PVdCs that may affectcapsule dimensions or dissolution profile, under hotand humid conditions.We recommend customers to select tight blisterssuch as aluminum/aluminum blisters to preserve theactive and the capsule, whatever the storageconditions.REFERENCES[1] International conference on harmonization oftechnical requirements for registration ofpharmaceuticals for human useCPMP/ICH/2736/99[2] USP General Chapter Dissolution[3] New modulated DSC measurement techniqueThermochimica Acta, Volume 402, Issues 1-2,3June 2003, Pages 91-98 Robert L. Danley;Modulated temperature differential scanningcalorimetry: A novel approach to pharmaceuticalthermal analysis International Journal ofPharmaceutics, Volume 135, Issues 1-2, 17 June1996, Pages 13-29 Nichola J. Coleman, DucanQ.M. CraigACKNOWLEDGEMENTWe wish to acknowledge the teams from theColmar Chemical R&D, Strasbourg PDC and Dr.Keith Hutchison for their support and discussions.Poster presented at the 2010 Annual Meeting and Exposition of the American Association of Pharmaceutical Scientists.New Orleans, LouisianaNovember 14-18, 20104/4Stability of Powder-Filled Hard Gelatin Capsules Stored in Standard I.C.H. Conditions- AAPS 2010- T3086