Regulating particle morphology during a spray freeze drying ...

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8 INTRODUCTION TO SPRAY FREEZE‐DRYING2.2 Spray freeze‐drying processThe typical solid dosage form for biopharmaceutical products is a lyophilized cake in aglass vial. The dried substances are reconstituted in water or buffer to be deliveredparenterally ‐ mostly using a syringe, but also a liquid jet injector is imaginable. Whendry powder is used for vaccination via EPI, conventional freeze‐drying is inappropriatefor particle preparation [Maa et al. 2003]. Certainly, the cake could be milled intosmaller fragments using a second manufacturing step, but the process yield would bereduced and the control of the particles´ properties and bioburden would be poor [Yu etal. 2002; Costantino et al. 2004]. Spray freeze‐drying of proteins is suitable to obtain fineand well‐characterized powders. SFD products are used to achieve sustained drugdelivery or to serve for specialized applications such as dry powder inhalation,intradermal or parenteral delivery [Maa et al. 1999; Sonner et al. 2002] ‐ also dissolutionenhancement for poorly water‐soluble drugs is possible [Leuemberger 2002]. Duringwater‐removal in SFD no substantial shrinkage of the frozen droplets occurs, contrary tothe evaporative water loss during SD [Masters 1991].Generally powder particles produced via SFD are not hollow as frequently observed withSD, despite their more porous character resulting from the freeze‐drying procedure[Maa et al. 1999]. The manufacturing process is composed of two consecutively appliedprocedures. First, the protein is dissolved in water or buffer to the desiredconcentration. The freshly‐prepared solution is atomized typically with an ultrasonicnozzle and directly sprayed into a bowl filled with chilled cryogen (e.g. LN 2 ). Second, theice of the almost instantly frozen, spherical particles is sublimated under vacuum in asubsequent lyophilization step [Maa et al. 2004]. The container filled with the dispersionof frozen spheres is transferred onto the pre‐cooled shelves of a freeze‐dryer, avoidingparticle thawing or melting. Once the cryogenic media is completely vapourized, thedehydration process can be iniciated [Sonner et al. 2002].Different excipients are added to the liquid feed in order to support theparenteral pharmaceutical form or to protect the protein/peptide during themanufacturing process (Table 2). Proteins can be damaged due to different stressesduring atomization, freezing or the subsequent water removal step in the freeze‐dryer[Costantino and Maa 2004] (Table 3).
INTRODUCTION TO SPRAY FREEZE‐DRYING 9Excipients for FD and SFDproductsDesired effect / mechanism• buffering agent control of the pH (different buffers: sodium citrate, sodiumphosphate, Tris(tromethamine) buffer)• stabilizing agento cryprotectant improve protein stability in aqueous solution and upon thefreezing step (PEG, sugars)o lyoprotectant improve protein stability upon lyophilization (water‐removal) andstorage (sucrose, lactose, trehalose)o anti‐oxidant free‐radical scavenger avoiding oxidative damage of the API(ascorbic acid, cystein HCl)o surfactant saturation of hydrophobic interfaces to protect proteins againstdenaturation, aggregation or binding (polysorbat 20 and 80,poloxamer 188)o chelators complexation of heavy metal ions, improving the efficiency of antioxidants(EDTA)• bulking agents structural enhancement of freeze‐dried products / increase ofmass for low dosed potent APIs (mannitol, dextran)• tonicity modifiers parenteral formulations are adjusted to be isotone on redispersal(NaCl, sucrose, mannitol)• antimicrobialpreservative agentsif multiple administrations from the same vial are intended, theformulation must be preserved to avoid microbial contamination(thiomersal, benzyl alcohol)Table 2.2004].Possible e used in FD or SFD products. Abstract list from [Constantinostress/events stress source potential mechanism(s) of damageatomization shear force protein conformation changesatomization air‐water interfaces protein adsorption and conformationchangesfreezing cold denaturation protein activity lossfreezing concentration and pH changes physical or chemical interactions due toenvironmental changesfreezing ice‐liquid interfaces protein adsorption and conformationchangesfreezing mechanical residual stress protein conformation changesdehydrationwater removal to disrupthydrogen bondingprotein conformation changesTable 3. Stress events associated with SFD [Costantino and Maa 2004].
Page 1: REGULATING PARTICLE MORPHOLOGY DURI
Page 4 and 5: IIFür meinen Großvater
Page 6 and 7: IVPetra Neubarth danke ich für die
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Page 10 and 11: IITABLE OF CONTENTS4 MATERIAL AND M
Page 12 and 13: IVTABLE OF CONTENTS5.4 Lactate Dehy
Page 14 and 15: VIABBREVIATIONSSmall lettersaacd pi
Page 16 and 17: VIIIABBREVIATIONSSEMSFDSFLSLSSSAUVs
Page 18 and 19: 2 INTRODUCTIONdrying (SFD) [Maa et
Page 20 and 21: 4 INTRODUCTION TO SPRAY FREEZE‐DR
Page 22 and 23: 6 INTRODUCTION TO SPRAY FREEZE‐DR
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Page 34 and 35: 18 LIGHT‐SCATTERING3 Light‐scat
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Page 44 and 45: 28 LIGHT‐SCATTERINGassure correct
Page 46 and 47: 30 LIGHT‐SCATTERINGThe positions
Page 48 and 49: 32LIGHT‐SCATTERING3.3.1Size exclu
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Page 52 and 53: 36 MATERIAL AND METHODS4.1.1.1 Bovi
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Page 58 and 59: 42MATERIAL AND METHODS4.2Methods4.2
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Page 68 and 69: 52 MATERIAL AND METHODS50 mM trizma
Page 70 and 71: 54 RESULTS AND DISCUSSIONAfter all
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58 RESULTS AND DISCUSSIONWhen calcu
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60 RESULTS AND DISCUSSIONcalibratio
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62 RESULTS AND DISCUSSION5.1.3 UV
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64 RESULTS AND DISCUSSIONFigure 41.
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66 RESULTS AND DISCUSSIONAn advanta
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68 RESULTS AND DISCUSSION5.1.6 Dete
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70 RESULTS AND DISCUSSIONa)b)Figure
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72 RESULTS AND DISCUSSIONIn additio
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74 RESULTS AND DISCUSSIONa) b)Figur
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76 RESULTS AND DISCUSSION5.1.9 Solv
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78 RESULTS AND DISCUSSIONthat could
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80 RESULTS AND DISCUSSION5.1.10 Eva
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82 RESULTS AND DISCUSSION5.2 Bovine
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486 RESULTS AND DISCUSSIONFigure 59
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88RESULTS AND DISCUSSIONFigure 62.
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92 RESULTS AND DISCUSSIONa) b)Figur
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94 RESULTS AND DISCUSSION5.3 SFD/SD
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96 RESULTS AND DISCUSSIONactivity l
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98 RESULTS AND DISCUSSION[Maa and P
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100 RESULTS AND DISCUSSIONTo avoid
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102 RESULTS AND DISCUSSIONIn contra
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104RESULTS AND DISCUSSIONFigure 78.
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108 RESULTS AND DISCUSSIONDuring al
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110 RESULTS AND DISCUSSION(Table 21
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112 RESULTS AND DISCUSSIONa) b)500
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116 RESULTS AND DISCUSSIONof Sonner
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118 RESULTS AND DISCUSSION5.3.4 SFD
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122 RESULTS AND DISCUSSIONincreasin
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126 RESULTS AND DISCUSSIONLF of dif
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132 RESULTS AND DISCUSSIONmore than
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134 RESULTS AND DISCUSSIONNeverthel
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136 RESULTS AND DISCUSSIONMolar mas
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138 RESULTS AND DISCUSSIONa)b)500
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142 RESULTS AND DISCUSSION5.3.5.2 C
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144 RESULTS AND DISCUSSIONAF4 and S
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146 RESULTS AND DISCUSSIONa)b)Figur
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150 RESULTS AND DISCUSSIONUV‐meas
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152 RESULTS AND DISCUSSIONstable an
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156 RESULTS AND DISCUSSIONpartially
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158 RESULTS AND DISCUSSIONdrying ca
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160 RESULTS AND DISCUSSION5.5.2 Cha
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162 RESULTS AND DISCUSSIONSFD parti
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164 RESULTS AND DISCUSSIONsalt comp
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166 RESULTS AND DISCUSSIONadditiona
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168 RESULTS AND DISCUSSIONThe addit
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170 RESULTS AND DISCUSSIONwith Hg p
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172 RESULTS AND DISCUSSIONon their
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174 RESULTS AND DISCUSSIONA change
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176 CONCLUSIONSand an UV‐B lamp w
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178 CONCLUSIONSLactic dehydrogenase
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180 ZUSAMMENFASSUNGConducted modifi
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182 ZUSAMMENFASSUNGes beim Lösen h
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184 ZUSAMMENFASSUNGAggregation oder
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186 REFERENCES8 References[Adler 19
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188 REFERENCES[Carpenter et al. 199
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190 REFERENCES[Dawson et al. 1964]
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192 REFERENCESInternational Journal
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194 REFERENCES[Kok and Rudin 1981][
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196 REFERENCES[Masters 1991]Masters
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198 REFERENCES[Pikal et al. 1990][P
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200 REFERENCES[Serrien et al. 1992]
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202 REFERENCES[Wahlund and Caldwell
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204 REFERENCES[Wyatt 2006a] Wyatt,
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206 CURRICULUM VITAE9 Curriculum Vi
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