Liquid Filling in Hard Gelatin Capsules - Preliminary Steps - Capsugel

Liquid filling in Hard Gelatin Capsules -Preliminary stepsD. Cadé & N. MaditCapsugel R&D, 68000 Colmar, FranceIntroductionFor more than 20 years, the liquid or semi solidfilling of Hard Gelatin Capsules have been routinelyperformed by the Pharmaceutical Industry. Amongthe various aspects of this technique, the selectionof the excipients or fills to be used remains a keystep of the development process. Preliminary stepsto be followed to identify suitable formulations arerecommended:• Determination of the water exchangeand control of visual aspect• Control of brittleness potential• Accelerated stability testing% water content 22° C302520151050Water absorptionWater desorption0 20 40 60 80 100% Relative HumidityDetermination of the water exchangeand control of visual aspectGelatin behaves as a hydrophilic polymer and assuch its water content may vary depending uponthe storage conditions. Equilibrium moisture, sorption- desorption isotherms have been described bymany authors. Depending on the previous moisture/dryinghistory the water equilibrium may bedescribed by the following hysteresis curve (Figure1). As long as the gelatin water content remains inthe range 11 to 16 %, no significant effect has to beexpected on capsules brittleness potential.Another aspect of the gelatin film which has tobe considered is its water vapour exchange. As anyfilm, the water vapour transfer can be determinedfor a gelatin film. Internal studies have demonstratedthat above a film thickness of 70 µm this phenomenonis constant. Our understanding is that thisphenomenon is mainly driven by water sorption/desorptionmechanism at the film surfaces. The transferof the water vapour within the film (above 70 µmthickness) is not a limiting factor (Figure 2).Figure 1: Gelatin Sorption IsothermP(mg.µmh/hmm2.mmHg)0.150.130.110.090.070.050 50 100 150 200Thickness (µm)Figure 2: Gelatin Water Vapour Transfer

The importance of this water vapour transfer canbe illustrated by the determination of the quantity ofwater absorbed by a hygroscopic dry powder (Carboxymethyl-CelluloseSodium salt from Sigma chemicalCo) filled into a Hard Gelatin Capsule stored at50 % RH / room temperature (Figure 3).B- Lauroglycol FCC (Chemical denomination:Propylene glycol laurate. Supplier: Gattefossé)(Figure 4).3HYGROSCOPICITY AFTER 4 WEEKSLOD(%) of CMC20181614121086Water exchange %210-1-2Smedds 1014/bisLauroglycol FCC4200 50 100 150 200Time (hour)Figure 3: Hard Gelatin Capsule Water PermeabilityMore important for the liquid formulation intoHard Gelatin Capsules is the determination of thewater exchanges as a function of the Relative Humidityof the ambient air. Screening tests have beendefined to identify a potential hygroscopicity of thefilled excipients by storage into dessicators atconstant RH.• 10 capsules are filled with the product to betested• These capsules are held in the upright positionand stored in dessicators at various relative humidities:2.5%, 10%, 30%, 50%, 65% RH• After 1, 2 & 4 weeks the water content changeis determined by weighing the capsules.-32.5 10 30 50 65Storage conditions % RhFigure 4: Water exchanges of two Gattefossé productsfilled into Hard Gelatin CapsulesAs per comparison other excipients have beentested for their hygroscopicity into Hard GelatinCapsules.Water exchanges in % w/w of excipients filledinto Hard Gelatin capsules stored 4 weeks atconstant Relative Humidity:Excipient 35%RH/RT 60%RH/RTPEG 300 +4.6 +14.7PEG 600 +2.9 +11.8PEG 4000 0 +0.6Glycerin +10.5 +28.2Empty capsules -0.4 +1.9Examples of products tested:A- Pharmaceutical formulation DH 1014/BisSolid SMEDDS from Gattefossé.Example with Gelucire products from Gattefossé:Excipient 10%RH/RT 65%RH/RT% w/wGelucire 44/14 80Plurol Oleique 10Lauroglycol FCC 10Gelucire 39/01 -0.8 +0.5Gelucire 43/01 -0.7 +0.4Gelucire 44/14 -1.0 +0.8Gelucire 50/02 -0.8 +0.7

As a first indication we would define suitability ofan excipient or a formulation for Hard Gelatin Capsulewhen water exchange is limited to -2% / +2%under above described test conditions.In parallel to this step, we recommend to controlthe visual aspects of the Hard Gelatin Capsules(softening or leakers).Control of brittleness potentialA second key aspect of the gelatin capsule stabilityto be determined is the possible trend for brittleness.Few authors have published on this characteristic(1). Capsugel method is based on thedetermination of the resistance to impact of theempty shells (measured with a modified Moutonpendulum - Figure 5). This technique gives an accurateinformation by testing a limited number ofsamples (N=10).Figure 7: Schematic view of a modified tube testerExample of resistance to impact of capsules(stored filled with various Gattefossé products)tested on individual body or cap parts:Loss on Resistancedrying to impact(%) (mJ/mm)SMEDDS 1014/Bis 12.2 27Lauroglycol FCC 12.4 25Acceptable range 12-15 >22Other methods have been described (2, 3) to determinethe potential brittleness of the capsulessuch as resistance to deformation of the filled capsules(Figure 6) or the tube test (Figure 7).Figure 5: Equipment for control of Capsule’sResistance to ImpactFigure 6: Test set up for capsule’s deformation testAccelerated stability testingA further step is the determination of the behaviourof capsules stored under accelerated stabilityconditions. From the various conditions recommendedby the ICH3 (4), we have selected as firstcondition to be tested the storage at 40°C/75% RH.We have selected the HDPE bottle as containerand checked the Hard Gelatin Capsules dissolutionstability after 1, 2, 3 and 6 months. Dissolutionmeasurements are performed on emptied capsulesrefilled with Acetaminophen (USP method).We have studied the dissolution behaviour of gelatinecapsules filled with lactose powder exposedto formaldehyde vapour (5). This technique did enableus and other authors to better understand theimportance of this mechanism (6). Capsules with

% Acetaminophen dissolved1009080706050403020100Reference13 ppm22 ppm HCHO41 ppm0 15 30 45 60Time in minutes% Acetaminophen dissolved1101009080706050403020100ReferenceSmedds 1014/BisLauroglycol FCC0 15 30 45 60 75Time in minutesFigure 8: Dissolution of Acetaminophen from capsulesstressed with various levels of formaldehydeand stored at 50°C for 4 weeksdelayed dissolution in water could easily be preparedin our laboratory and tested with Acetaminophen(Figure 8).Using the same approach, we have filled our gelatinecapsules with various products selected fromthe range of excipients from Gattefossé and storedthe filled capsules at 40°C / 75 % RH. After the definedperiod (1,2,3 & 6 months) the capsules areemptied from their fill and refilled with Acetaminophento perform the dissolution test described. Resultsbelow (Figure 9), show that there is no interactionbetween the SMEDDS 1014/Bis or theLauroglycol FCC and the gelatine capsules.Figure 9: Dissolution of Acetaminophen from capsulesstored at 40°C/75%RH with various fillsConclusionThe results obtained with the selected tests aresummarized below.With the three steps described above, preliminaryselection of the appropriate excipient formulationfor liquid or semi-solid filling into Hard GelatinCapsules, can be performed at an early developmentstage, in the laboratory, without involving highcost or sophisticated equipment.Solid SMEDDSLauroglycol1014/BisFCCWater loss / gain Less than 2% Less than 2%Visual aspect No change No changeBrittleness Within range Within rangeAccelerated stability 40°C/75% RH - Dissolution No change No changeReferences1. Mark J. Kontny and Carol A. Mulsky, Intern. Journal of Pharmaceutics, 54 (1989), 79-852. D. Cadé, APGI Colloque Nov 1994, Chatenay - Malabry, France3. T. Yamamoto and all, Pharm. Tech. Japan, Vol. 8, N°11, 19924. Eur. J. Pharm. Biopharm. 41 (3), 194-195, 19955. D. Cadé, N. Madit and E.T. Cole, AAPS Pharm. Research Vol. 11, No. 10, p. S 1476. G.A. Digenis; T.B. Gold; V.P. Shah; Journal of Pharmaceutical Sciences, 83 (7), 915-921, 1994®BAS 191 E 1998