_2___§e_.s_§§=852$
`
`HruomeMT
`
`FRESENIUS KABI 1011-0001
`
`

`
`Library of Congress Cata1oging- in - Publication Data
`
`Pharmaceutical dosage forms, parenteral medications I edited by
`Kenneth E. Avis, Herbert A. Lieberman, and Leon Lschman. —- 2nd ed.,
`
`|
`.
`
`1_
`
`rev. and expanded.
`p.
`cm.
`Inciudes bibliograpl-deal references and index.
`ISBN 0-3247-95764 {v. 1 2 alk. paper)
`1. Parenteral solutions.
`2. Pharmaceutical technology.
`Kenneth E.
`II. Lieberman. Herbert A.
`III. Lachman. Leon.
`[DN1‘..M: 1. Infusions, Parenteral.
`WB 354 P5361
`RS2fl1.P3‘7P-18 1992
`615‘. 19--dc2D
`DNLMIDLC
`for Library of Congress
`
`I. Avis,
`
`V
`2. Technology. Pharmaceutical.
`
`31 ‘33053CIP
`
`This book is printed on acid-free paper.
`
`CGpyrlghl© 1992 by MAIICEL DEKKER, INC. All Rights Reserved
`
`Neither this book nor any pan may be reproduced or uansmined in any form
`or by any means. electronic or mechanical. inciuding photocopying. micro-
`filming. and recording, or by any information storage and retrieval system,
`without permission in writing from the publisher.
`
`MARCEL DEKKER. INC.
`210 Madison Avenue, New York, New York 10016
`
`Current printing (inst digit):
`[0 9 B T 6 5 4 3 2
`l
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`FRESENIUS KABI 1011-0002
`
`

`
`Formulation Of Sfllflfl Volume Ptjrentgr-Q13
`
`21?
`
`
`
`
`
`WATERCONTENT.‘K:
`
`moles
`
`
`
`WATERCONTENT,
`
`U
`
`In
`
`In
`an
`50
`an
`an
`20
`PEHCENT BELATH.-‘E HUMLDITY
`
`.83
`
`all
`
`Figure 20 Relative humidity versus water content of hydrate forms of sodium
`cefazolln. —o-o—o-. Monohydrate; —o—o—o-_ sesquihydl-ate; —o—-A-—a.— _ penta-
`hydrate.
`(From Ref. 40.)
`
`Fr-eeze—Drying. From a historical standpoint the process of fres-.ze— drying.
`often referred to as Iyophilizotion. received its initial thrust during World War
`II when whole blood and blood plasma became lifesaving elements. and adequate
`supplies were jeopardized because of stability and shipping problems associ-
`ated with these natural biological products. Soon after World War II, the phar-
`maceutical industry began considering the process for the preparation of sterile
`injeoteble dosage forms which could not be formulated into stable solutions.
`At the same time the food industry began employing freeze-drying to process
`and package foods, an application that continues to grow. Another application
`that has been receiving research attention is the preservation of biological
`substances, especially those of high worth or in short supply. Vital organs
`and tissues are also preserved by freeze-drying. Substances that degrade
`in solution become candidates for freeze-drying. This precludes storage of
`the product in a deep-frozen state which presents solubility problems, is cost-
`ly. and there is always the risk of degradation. Often, fz'eeze~dr-ying offers
`the only means to stabilize the product or may he a convenient way to stock-
`pile material for defense or emergency purposes and of course shipment and
`storage of dry material are less expensive than that in solution form. Although
`there are those who would consider freeze-drying only as the last resort.
`there are others who view it as a pana.cea—a way to get into clinical trials
`quickly or a way to exclude contaminants and inert particles, especially in
`comparison with powder Filing. Certainly.'freeze—d.1"ylng does offer the ad-
`
`FRESENIUS KABI 1011-0003
`
`

`
`21 3
`
`DeLuco and Boylon
`
`
`
`l.l0|Jl|I| FEED Am HEATER
`5/
`RTDMIZEH
`EXHMJST
`
`
`‘
`srnnv
`
`Pfiuusléenusr mu
`mm
`"“"“3E" ~
`cnutctun
`
`
`
`
`mm
`
`Figure 21 Schematic drawing of spray dryer,
`
`um
`mount
`
`vantage over powder filling of accuracy of dosage, since the drug is filled
`Into the final container as a solution. Microgram quantifies can be filled pre-
`cisely. Powder filling is used where the required dosage is represented by
`a large quantity of the drug or‘ where the solubility is not adequate to ireeze
`and as previously described with powder filling. sterilization of the powder
`is possible prior to filling.
`(1) dis-
`The process of freeze-drying illustrated in Figure 22 involves:
`solving the drug and excipiente in a suitable solvent , generally water; (2)
`sterilizing the bulk solution by passing it through a bacterle—retentive filter;
`(3) filling into individual sterile: containers; (4) freezing the solution by place
`ing the open containers on cooled shelves in a free:e—drying chamber or pre-
`freezing in another chamber; and (5) applying a. vacuum to the chamber and
`heating the shelves in order to sublime the water from the frozen state. The
`desired characteristics of at freeze-dried pharmaceutical dosage form include:
`(1) an intact cake occupying the sa’me shape and size as the orig-inal frozen
`mass; (2) sufficient strength to prevent cracldng. pondering. or collapse:
`(3) uniform color and consistency; (4) sufficient dryness to maintain stability;
`and (5) sufficient porosity and surface area to permit rapid reconstitution.
`Of course. as with any injectable dosage form, freedom from contamination
`(i.e., microorganisms. pyrogens, and particulates) is an essential attribute.
`The desired characteristics can be achieved by proper formulation of the
`product and by employing optimum freeze-drying cycles. The development
`of a suitable formulation and a. freeze-dry cycle requires knowledge of some
`basic properties. such as:
`(1) eutectic temperature; (2) temperature effect
`on solubility; (3) thermal properties of the frozen solution: (4) degree of
`supercooling: (5) heat transfer properties of the freeze-dryer shelves. metal
`trays, glass vials, and the frozen product; and (6) equipment design and
`equipment capability. Formulating the solution to be freeze-dried must be
`done with a View toward the characteristics requzired at the time of reconstitu-
`tion and administration. The drug alone often does not provide the solid con-v
`tent or characteristics appropriate for the finished product, and inert or rclow
`tively inert substances such as lactose or mannito] must be added prior to
`freeze-«drying to provide the necessary bulk and desired characteristics.
`
`FRESENIUS KABI 1011-0004
`
`

`
`Formulation of Small‘ Volume Parenter-als
`
`219
`
`DISSOLVI NG
`MATERIAL
`
`ASEPTIC
`FlLTRflTlON
`
`FILLING
`
`FREEZE
`DRY I MG
`
`JI
`
`ll
`0'
`
`1-2
`
`
`
`I
`
`STDIEIUTY 0 RAPID SOLUBILITY 4- ELEGANCE
`
`Figure 22 Freeze-drying process.
`
`For a systematic approach to the development of 9. suitable freeze-'dfied
`product, knowledge of the various stages of the process is necessary. The
`main stages can be classified as freezing and drying. The initial freezing
`process is of critical importance since it will influence the pattern of the sub-
`limation phase. The latter phase must occur [1-oru the solid state throughout
`the cycle. Appropriate cooling cycles must be determined in order to obtain
`an appropriate structure of the frozen mass. which is a function of the rate
`of freezing and the final freezing temperature. The rate of freezing also ef-
`fects the size of ice crystals. The slower the rate of freezing, the larger
`the ice crystals that form. Freezing of the solution is most conveniently ac-
`complished in the chamber to be employed for drying, by placing the contain-
`ers of solution on a shelf that is cooled by a circulating‘ refrigerant, such as
`Freon. Ccllueolve, or trichlorethylene.
`If the frozen system exhibits meta-
`stable or morphous-glassy structures, these structures may need to be rup-
`tured by appropriate thermal treatments (a succession of cooling and rewerrning
`periods), thereby inducing‘ crystallization of the amorphous material and ade-
`quate crystal size necessary for efficient sublimation.
`The most commonly employed method of drying pharmaceuticals is conden-
`sation at low temperatures whereby. through the principal mode of conduction.
`heat is transferred to the frozen product to effect vaporization. By further
`introducing a cold surface into the system at a temperature below that of the
`frozen product, the water vapor evolved by the drying nlateritil will be cork
`danced as ice on the refrigerated surface. The process is illustrated in Fig-
`ure 23, together with the temperature gradient during the drying cycle. Puc-
`tors influencing the rate of vaporization have been discussed extensively [67,
`G8] . The faster heat can be applied, the faster the drying proceeds, pro-
`vided that (1) the temperature of the product remains below its Iiquefying
`point, and (2) a sufficiently low pressure is maintained in the system by ef-
`ficient vacuum pumps.
`If a sufficiently low pressmre is not maintained, the
`temperature of the product will rise until a phase separation occurs. resulting
`in the partial softening or puffing of the pfcduct.
`
`FRESENIUS KABI 1011-0005
`
`

`
`229
`
`.DeLu.ca. and Boylon
`
`__
`
`-—— couoewsea
`
`
`
`DRY MATERIAL
`
`DRYING 8 UR FACE
`F ROZEN MAT ERIA L
`
`HEATING SHELF
`
`Figure 23 Drying process during freeze-drying. The temperature gradient
`is shelf > dry material > drying surface > frozen material > condenser.
`
`In developing a formulation for i'reeze-drying. the optimal formula will
`permit the overall cycle to be carried out in the least amount of time, while
`providing a stable and efficacious product which contains a low moisture con-
`tent, undergoes rapid reconstitution, and possesses the desired appearance.
`The potency of many pharmaceutical agents is of such magnitude that relative—
`137 small amounts are required for the lyophilioed injectablc dosage form. There-
`fore, the need for a suitable filler or bulking agent is often indicated. The
`percentage of solids in the frozen plug will vary depending on the dosage and
`nature of the active ingredient; generally, it should be above 5% and not ex-
`ceed 30%. with a 10 to 15% content being optimum . Materials to choose from
`to add to the solution to Improve the physical characteristics of the finished
`cake are limited but include gelatin. mannitol. lactose, sucrose, dextran. sorbi-
`tol, mono- and dibasic sodium phosphate, calcium lactobionate, bovine serum
`albumin, and sodium chloride.
`It should be kept in mind when adding bulking
`agents that drying will be accelerated if the solute concentration is kept low.
`If degradation is a risk during freezing due to concentration effects or pH
`changes. stabilizers or buffers may have to be added. The problem of collapse
`has been discussed earlier and if the substance is vulnerable to collapse, a
`1-igidizar such as glycine or mannitol may need to be added. Again it is im-
`portant to point out that dilution is also a way to avoid meltbnck and collapse.
`So compromises’ and trade-offs are often necessary.
`It damage during frees-
`ing is a problem. a cryo-protective agent such as bovine serum albumin may
`be added or to minimize damage due to overdrying, sugars have been added.
`If the ingredients that are added are found to adhere to the glass surface.
`such as albumin. than the containers with thin walls, such as ampuls and tubu-
`lar vials, may need to be coated with silicone to minimize cracking. The depth
`of fill in a container is critical. While this depends on the volume of the con-
`tainer, a rule of thumb has been 1 to 2 cm in depth but never exceed one-half
`the capacity of the container.
`
`FRESENIUS KABI 1011-0006
`
`

`
`Formulation of Small Volume Parenterals
`
`221
`
`Most freezewlried drug products are orctgnic electrolytes which exhibit
`eutectic points and super-cooiing tendencies. Several methods have ‘been used
`for determining eutectic temperatures:
`(1) thermal analysis; (2) differential
`thermal 311313919: and (3) electric resistivity. The electric resistivity method
`[$9. 70] involves the simultaneous monitoring of resistance and temperature of
`a frozen sample. Below the eutectic temperature the resistivity is very high,
`but when the eutectic is reached there will be a sudden change in resistivity
`due to a phase change and occurrence of liquid in the mass. An advantage
`of the resistance method is that not only can eutectic temperature be deter»
`mined but the degree of supercooling and other phenomenon, such as recrys-
`tallization. can be assessed.
`Examples of freezing and thawing curves are shown in Figure 24 for a
`1.0 molar solution of an inorganic electrolyte, sodium chloride. together with
`the warming curve for pure water. For sodium chloride. the extent of super-
`cooling is shown to be very significant with solidification occurring at about
`-30°C.
`In the event that the cooling curve was used to measure eutectic tem-
`perature , inaccurate information would be obtained as a result of the super-
`cooling effect. The true eutectic temperature. as seen from the warming‘ curve
`
`105
`
`we
`
`RESISTANCERC
`
`(EUTEc1':c1
`-215°C
`
`1
`
`{FREEZING POINT}
`-3.9°c
`0° C
`
`I
`
`WARMING cunvs
`
`FOR PUFIE WATER
`‘I
`
`RECRYSTALLIZATHON
`-:»:-I-‘
`
`
`20
`40
`an
`140
`120
`mu
`so
`cl-4AHTDIVIS1ONt-nml —I-T“C=U.1423 lm-11“-1°31
`
`0
`
`Figure 214 Resis-1ance—temperature curves for the freezing and thawing of 1. 0
`M sodium chloride solution.
`[From P. P. DeLuca and L. Lachmsn, J. Pharm.
`Sci., 54:14:12 (19e5).]
`
`FRESENIUS KABI 1011-0007
`
`

`
`222
`
`DeLucu and Boylcm
`
`105
`
`COOLING
`CURVE
`
`RESISTANCE,Q
`
`105
`
`
`
`WARMING
`CURVE
`
`-25° -20° 45° 40° -5°
`TEMPERATURE. °c
`
`u
`
`Figure 25 Cooling and warming curves for CI. 3 M mcthylphenidate HC1 so1u~
`tion.
`(From Ref. 59.)
`
`in the figure, occurs at —21.6°C. The eutectic temperature is obtained from
`the warming curve at the point where there is a sudden drop in resistivity
`or. conversely, an increase in conductivity, due to the occurrence of liquid
`in the cell containing the frozen mass. The curves shown in Figure 25 for an
`organic pharmaceutical, msthylphcnidate hydrochloride. are somewhat more
`complex than those obtained for the inorganic electrolyte. Nevertheless, the
`eutectic point (-11.7°C) can be determined from the sudden change in 1-aeitiv—
`ity , indicating a phase transition.
`A knowledge of the eutectic temperature of the additive is essential since
`the addition of a salt such as sodium chloride to a drug With a eutectic signifi-
`cantly abovc that of sodium chloride wouJd only succeed in lengthening the
`Cycle because lower tempo:-aturefi would have to be maintained.
`In addition.
`some additives, such as sodium chloride and the phosphates. tend to form
`crusty-appearing cakes. This occurs during freezing and drying, probably
`because of the phenomenon of recrystallization. Volatile substances are gen-
`erally considered to be of little value to the finished cake but can be used if
`they accelerate the drying cycle. Dioxane, ethanol. t-butonol, dimethyl sulf-
`oxide (DMSO). and acetone are examples.
`Antimicrobial agents such as phenol, chlorobutanol, and benzyl alcohol
`serve only to preserve the solution prior to freeze-drying. One must remem-
`ber that if a. volatita substance is used for a temporary effect, complete remov-
`al of the substance from the finished cake must be substantiated through ade-
`
`FRESENIUS KABI 1011-0008
`
`

`
`Formulation of Small Volume Parentcrals
`
`323
`
`quote testing. The retention of volatile substances has been found to Qccup
`during the freeze-drying of liquid and ecmiliquid foods,
`For compounds that do not form true eutectics, the variations of tempera-
`ture in s freeze-dryer often result in a finished product of varying quality.
`Meltbsck. discoloration, and collapse are occurrences that necessitate rejec-
`tion of all or parts of the batch. Quite often e substance is not considered
`to be a good candidate for freeze-drying and the process is discarded. Phase
`transitions that occur in the frozen state have been shown to influence the
`properties of the dried product [71] . Cefszolin sodium. commercially avail-
`able as s freeze-dried product, freezes as the amorphous form and unless
`thermally treated to effect crystallization will remain in the less desirable amor-
`phous state. Figure 26:; is a therrnc-gram obtained by differential scanning
`calorimetry for cefszolin sodium. The first endothermic shift occurs at -20°C
`(point B), an irreversible exotherm begins at —11°C (point C}. and melting
`of ice begins at -490 (point F). considering the portion of the curve begin-
`ning just below the initial endotherm and to just above the irreversible exo-
`therm. if warming were to proceed to just beyond the exctherm , say — 6°C .
`and the system recoolsd to —25°C. upon 1-swarming, the dashed curve shown
`in Figure 251:, would result. This indicates that the frozen material has under-
`gone transition.
`If. however. cefazolln was £2-ozen and dried below —22°C
`(presumably the glass transition temperature). with no thermal treatment. the
`resulting product would be amorphous. This was confirmed using optical micro-
`scopy. scanning electron microscopy, and x-ray diffraction on freeze- dried
`material that was dried with and without thermal treatment. Material treated
`at —1D°C exhibit birefrigencaa under crossed polars, defined shape by scanning
`electron microscopy (Fig. 27) and an x-ray diffraction pattern o0J1SiSTm§ Uf
`peaks of various intensity. All of these are indications of crystalline struc--
`ture. Kinetic studies show that the crystallization can occur above -20°C
`(point B in Fig. 26b) and is very rapid above - 11°C (point C).
`
`Af‘!lP‘l-115
`Freeze-dried products are generally packaged in ampuls or vials.
`would only be used for slnglewlose administration. and provide even drinng
`because the tubing is thin and bottoms are reasonably flat. Howcirer, they
`must be sealed after removal from the chamber and reconstitution ls sorneftmefi
`cumbersome if shaking is required. Additionally, the generation of glass pal‘-
`ticles is a problem. Vial are used for both single-- and ml11fiP1e'<1°SB “PP”-°3'
`tion.
`If molded glass is used. there is greater incidence of lvariation of thiclr
`ness and uneven bottoms. The containers must be sealed with a closure lhat
`can be accomplished inside the chamber, lessening‘ the risk of contamination
`and providing an opportunity to seal under an inert gas or under vacuum-
`
`Reconstitution is much easier. but there is the risk of introducing-rubber
`particles. Butyl rubber is preferred over neoprene due to low moisture Vapor
`transmission.
`_
`Temperature and pressure curves for a tpyical cycle are illustrated 111
`Figure 28. with the circulating temperature set at 60°C, all the P"°bed 53"“
`pies passed through 0°C within 6.5 hr. The heat was lowered gradually to
`40°C and allowed to remain at this temperature until the run‘ was termmnted.
`From the temperature and pressure curves. it can be seen that maximum dry‘
`lug; took place between 1 and G hr. The maximum VaP01‘ PNSSUT‘? d1f£°r°n°°
`between chamber and condenser occurred between 2 and 5 hr, with the cham-
`ber Pressure reaching a minimum value of 15 um after 10 hr. The leveling
`
`FRESENIUS KABI 1011-0009
`
`

`
`224
`
`Debuca and Boylan
`
` GEFAZULIN. SODIUM
`
`29 ‘I15 “fw
`Cnated toolmin: Wavmad ‘l.!5°a’m‘1n
`Rang: 2
`
`man!J’n:
`
`L ENDOTHERIJI
`
` A_*_l_
`~70
`-30
`-50
`~40
`-30
`~20‘
`430
`D
`DFGREESCENTJGHADE
`
`lbl
`
`«loathe:
`
`ENDDTHERM
`___|__.I.___..._.I_:_..r__._._....J._
`-33
`.20
`.15»
`I0
`DEGREES CENITKGRADE
`
`Figure 26 DSC thermogram for the warming of a frozen cafazolln sodium solu-
`tion.
`(8) Temperature range between 0 and -70°C.
`(b) Endothermic and exo-
`thermic araas of the thermograrn of cefazolin sodium. Solid curve corresponds
`to warming following freezing to —3U°C; dashed line corresponds to the warm-
`ing curve of the previous solution which was re-cooled after warming" to -6°C.
`(From Ref. 71.)
`
`FRESENIUS KABI 1011-0010
`
`

`
` SID-153149-alfldSILCYIIOAHIJIHSJDUORDIHWJOJ
`
`
`
`
`
`(3) Dried without thermal treatment.
`Figure 2? Scanning electron micrographs of freeze-dried cefamlin sodium.
`(b) Frozen mass warmed to -10°C and held 15 min before cooling 8-[Id drying. Original magnificafion:
`1200 X 10
`31V.
`{F1-om Ref. 11.)
`
`932
`
`FRESENIUS KABI 1011-0011
`
`

`
`DeLuca and Eoyfan
`
`smzu= remreripzfune
`
`c'_.u.........
`
`I_.-'
`1‘
`1,.’
`
`AVE. PRODUCT
`TEMPERATURE
`
`CHAMBER PRESSURE
`
`. - ' '
`
`.....
`
`‘ ' ' - u.
`
`:
`;
`2
`-.
`3
`1
`
`_a'
`
`I’
`
`‘..'
`
`CONDENSER
`PRESSURE
`
`226
`
`+50
`
`+411
`
`«.3O
`
`E *2!)
`E’4u:
`E
`5ID
`:-
`
`0
`
`_2o
`
`~40
`
`1'20
`
`100‘
`
`90
`
`5”
`
`40
`
`20
`
`Ev
`
`1 u
`
`‘ E
`
`ILI
`as
`n:
`E.
`
`0
`
`0
`
`2
`
`4
`
`6
`
`B
`
`10
`
`TIME. hr
`
`Figure: 28 Temperature-time and pressure-time curves characteristic of the
`[From P. P. DeLuca, J.
`drying cycle for ms-thylphenidate hydrochloride.
`-]
`Pharm. Sci. . 5'0: 773 (1971)
`
`FRESENIUS KABI 1011-0012