Pharmaceutical Technology: Fundamental Pharmaceutics

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Pharmaceutical Technology Fundamental Pharmaceutics

Copyright © 1970 by Burgess Publishing Company All rights reserved Printed in the United States of America Library of Congress Catalog Card Number 70-92313 Standard Book Number 8087-1628-X Second Printing 1970 Third Printing 1971

PREFACE Pharmaceutical Technology is not an encyclopedic reference book; it is a textbook designed for the undergraduate student who has completed the required mathematics, organic chemistry, physics, and zoology. It contains the minimum pharmaceutical information and knowledge required as a prerequisite to the dispensing pharmacy course and to the proper practice of any occupational aspect of pharmacy. Pharmaceutical Technology quantitatively correlates physicochemical theories with the char­ acterization, development, evaluation, and preparation of dosage forms. The general objectives of courses in pharmaceutical technology are: 1. To impart a comprehension of chemical and physical principles pertinent to pharmaceutical phenomena, preparations, and problems, which can be used to understand and predict the behavior and efficacy of pharmaceuticals. 2. To develop skills and techniques upon which pharmaceutical processes are dependent through actual use of equipment, instruments, and laboratory manipulations. 3. To present professional and scientific terminology that will enable the pharmacist to express himself as an educated person as well as to read current literature. 4. To promote judgment based on critical, logical, and imaginative thought. The discipline of pharmaceutical technology can be conveniently studied according to physical state: solids, solutions, and polyphasic and plastic systems. A schedule of three lectures and one labora­ tory weekly for a minimum of two semesters (preferably for three semesters) permits satisfactory cover­ age. For the interested teacher further discussions are found in Proceedings Teachers’ Seminar on Pharmacy 13, 38 (1961); American Journal o f Pharmaceutical Education 27, 198 (1963); and A. A. C. P., Studies o f a Core Curriculum, 1968. The objectives of a course in pharmaceutical technology cannot be achieved without a labora­ tory. The laboratory exercises should be designed to simultaneously correlate theory with pharmaceuti­ cal applications so that the student identifies the theory to be learned with a recognized need for it. The use of Experimental Pharmaceutical Technology in the laboratory facilitates the presentation of labora­ tory exercises concurrently with the discussion and theory presented in this book. In the experience of the author the undergraduate student rarely reads references; thus, the traditional references are not provided. For those persons interested in additional reading, the references accompanying the figures and the references in the companion book, Experimental Pharmaceutical Technology, are helpful. The centimeter-gram-second system is used with few exceptions. All un­ specified temperatures are expressed in the centigrade scale. More than 170 simple drawings are^used to facilitate understanding of a relationship or the operation of equipment without the distraction of nonessential details. Seventy tables and 111 formulations are used to present specific examples to sup­ port the discussions. A concise review of mathematics is given in the Appendix. It is intended that the student study this book with the concept that it contains core knowl­ edge. The lecturer varies emphasis and presents facts in addition to this core knowledge according to his educational philosophy and experience and according to the curriculum of the individual college. Eugene L. Parrott iii

C O N T EN T S Page Preface ................................................................................................................ Symbols and Physical Constants......................................................................... Part

vn

1. Solids

Chapter Chapter Chapter Chapter

1. 2. 3. 4.

1 Characteristics of Particles and Powders............................................................. 37 Comminution and Blending of Solids . , ........................................................... Solid Pharmaceuticals ........................................................................................ 58 Properties of S o lid s............ ................................................................................ 107

Part II. Solutions

Chapter Chapter Chapter Chapter Chapter Chapter

5. 6. 7. 8. 9. 10.

Characteristics of Solutions . r ............................................................................. 139 Dissolution Processes........................................................................................... 158 Aqueous Pharmaceutical Solutions..................................................................... 170 Nonaqueous Pharmaceutical Solutions....................................................................238 Chemical Stability................................................................................................. 250 ' Sterile Solutions..................................................................................................... 274

Part III. Polyphasic and Plastic Systems

Chapter Chapter Chapter Chapter

11. 12. 13. 14.

Characteristics of Polyphasic System s....................................................................295 Dispersion Processes .................................χ·.......................................................... 317 Fluid Pharmaceutical Suspensions and Emulsions ................................................ 341 Plastic Pharmaceutical Suspensions and Emulsions................................................ 364 Appendix

395

Index

409

v

SYM BOLS AND P H Y S IC A L C O N S T A N T S A

absorbance; area '■

A

angstrom unit (IO’8 cm)-

C

capacitance; concentration; number of components

D

diffusion coefficient (cm2 sec - 1 ); debye (1 O’1 8 esu cm)

E

energy; voltage -

Ea F

activation energy_

G

free energy

ΔΗ

activation energy; heat of solution

J

joule

K

absolute temperature scale; equilibrium constant; partition coefficient

Kb

boiling-point constant (deg molal- 1 )

K

freezing-point constant (deg molal'1 )

f

number of degrees of freedom ·

L

freezing-point constant (L = iKfp, specific conductance (ohm '1 cm ' 1 )

M

molecular weight (g mole- 1 ); molarity

N

Avogadro number (6.024 X 102 3 mole’1 ); mole fraction; normality

P

number of phases; polarization; pressure

Q R

flux (mass cm’2 sec- 1 ) gas constant (0.0821 liter atm mole-1 deg- 1 ; 1.987 cal mole-1 deg- 1 ; 8.315 X 107 ergs mole-1 deg- 1 )

S

area; solubility; specific surface

T

absolute temperature (i + 273)

ATf

freezing-point depression

V

volume of 1 mole of a gas; volt

W

work

a

activity; radius of atom or ion

atm

atmosphere (14.7 lb in.- 2 = 760 mm of mercury)

c

concentration vii

cal

caloric * 4.184 absolute joules

ct

cubic centimeter (c m 1)

cm

centimeter

cp

centipoise

d

diameter

deg

degree

e

electron; electronic charge

f

force; fraction

g

acceleration of gravity (980 cm sec )

g

gram

h

height; thickness

hr

hour

i

van’t Hoff factor

k

Boltzmann constant (Λ/TV = 1.38 X IO’ 1 6 ergs deg’1 m olecule'1 ); reactionrate constant

kcal

kilocalorie (1000 cal)

kg

kilogram (1000 g)

/

equivalent conductance of an ion; length

Zn

2.303 log

m

mass; molality

min

minute

πψ.

millimicron (IO -7 cm)

n o

number of moles; number of particles; transference num ber as a subscript refers to variable in its pure state or its initial value

P

partial pressure

P

poise

PH

expression of hydrogen ion concentration; -log a ^ +

pX

-log a:

psi

lb in."2

Q

flux (mass cm"2 sec’ 1 )

r

radius

sec

second

t

centrigrade temperature; time

•'A

half-life

V

volume

w

weight

z

valence of an ion viii

Alcohol Cellulose derivatives Gelatin · Glucose Polyvinylpyrrolidone Starch J Sugar Water

Percentage of Granulating Fluid 10-20 5-10 , 10-20 25-50 3-15 5-10 70-85

/

v i'

-

With the potent, synthetic medicinal chemicals used today, the active ingredient often constitutes only a small part o f the total tablet. A diluent is then used to increase the bulk of the tablet to a convenient size. Common pharmaceutical diluents are calcium carbonate, calcium sulfate dihydrate, dicalcium phosphate, glycine, mannitol, and lactose. In industrial pharmacy, a batch ticket or photocopy is made of a master formula to avoid errors in transposition. By appropriate use of the batch ticket the ingredients are ordered and delivered to the production area. Each ingredient is checked and weighed by at least two persons. All ingredients are reduced to a powder and mechanically blended by standard mixing techniques (see Chapter 2). Granulation is important, as it is this step in the process that determines the operation of the tablet machine and the properties of the tablet. By choosing a suitable granulating solution in the correct am ount, the fine powder is converted into a granular form that will flow freely and uniformly from the hopper to the die cavity while possessing adhesive properties. In small developmental batches the granulating solution is added gradually with kneading. The mass should no t feel sticky, but it should form a ball when squeezed in the hand. Excessive granulating solution will cause the mass to become sticky so that it will be difficult to pass through a screen during the granulation process and will require a longer drying time. Excessive granulating solution may also make a hard tablet with a long disintegrating time. Insufficient binder leads to poor adhesion with capped tablets, i.e., tablets with the tops split.

76

·

solid phiitmactmllcals

The granulating solution is blended Ihoiouglily into the mass by use of a ribbon or other suitable blvndet. the wet mass is passed through a screen, e.g., 6 Io 8 mesh, by an oscillating granulator or a hanunct mill, and the wel gi.mules are collected on n paper-lined tray. Ibc granules aie spiead on a tray m u layer not exceeding !Zt in. and arc placed in a drying oven with cncnlatjng air al 40 1o 60°. The grannies must be dry before compression or they will stick Io the punches and die. A drying cycle varies from 6 to 18 hours. Very rapid oven drying is avoided, as the outsides of the granules will lose their moisture first and bake to a hard shell, which will prevent the moisture from escaping ftom the interior. Upon compression the granule is broken and the liberated moisture will cause the punches to stick. The oven-dried granules are reduced in size depending on the dimensions of the finished tablet. For small tablets, e.g., % in., a 30-inesh granule is prepared; for large tablets, e.g., 7/16 in., a 12-mcsh granule is prepared. With a colored tablet or an imprinted tablet, a granulation as small as 40 mesh may be used to avoid a mottled coloring or imperfect lettering. An oscillating granulator or a hammer mill is used to reduce particle size, because as soon as a particle is reduced to the desired size, it falls through the screen away from the grinding action and is not further reduced in size. Grinding-type granulators and comminutors tend to fracture the granules and produce an excess of fines. A tablet machine measures the amount of granulation to be compressed into a single tablet by volume, i.e., the fill of the die cavity above the lower punch. The size frequency distribution o f the granulation should be moderately narrow, with some small particles to fill the interparticular spaces so that each delivery of granulation to the die will have the same weight and uniform tablets will be produced. Ideally, the granules should approach a spherical shape so that they will flow readily. The angle of repose gives some indication of how well these goals have been attained. A lubricant is a substance that is added to the granulation to aid in the flow o f the granulation, to reduce die wall friction, to prevent sticking to the surface of the punches and die, and to aid in ejection of the finished tablet. A lubricant has a high specific surface, which enables it to coat a large number of granules. Lubricants are usually passed through a 200-mesh sieve to ensure their small particle size. The amount of the lubricant employed should not exceed 1 per cent. Common lubricants are calcium stearate, glycine, magnesium stearate, stearic acid, Sterotex®, and talc. A disintegrating agent is added to the granulation to cause the tablet to rupture into small particles in the gastrointestinal tract. The large number of small particles present a greater surface to the dissolving fluid than an intact tablet does; therefore, the drug dissolves more rapidly and is absorbed faster. The common disintegrating agent, e.g., starch or algins, absorbs moisture and swells, causing the tablet to disintegrate. Dried starch is the most used disintegrating agent; it should be dried at 100° to remove the water that has been absorbed from the atmosphere. The lubricant and the disintegrating agent are added to the granulation and gently mixed so the granules are not broken. The formulation is now ready for compression. A single-punch tablet machine consists fundamentally of a die fitted with an upper and lower punch as shown in Figure 41. By means of cams the machine is engineered so that when the upper punch is out of the die, the lower punch is at its lowest position and the feed shoe connected to the hopper is filling the die cavity with granulation. The height o f the lower punch may be adjusted to control the size of the die cavity and hence the weight of the tablet. As the feed shoe withdraws, the upper punch descends compressing the granulation in the die cavity. The upper punch forms the upper surface of the tablet, and the lower punch forms the lower surface of the tablet. The upper punch now begins to rise, and after a brief lag the lower punch begins to rise. As the lower punch rises it pushes the tablet from the die. The lower punch rises until it is flush with the upper surface of the die. The feed shoe ejects the tablet and then fills the die cavity as the lower punch descends. The height to which the lower punch rises is adjustable. If it were too low, the feed shoe would split or cap the tablet during ejection. If it were too high, the feed shoe would strike the lower punch with mutual damage.

solid pharmaceuticals

Ftgurp 41. Compression cycle for a single­ punch tablet machine: (al granulation f ill­ ing die cavity: (bl granules are compressed into a tablet; (c) tablet is pushed from die cavity by lower punch; (d) tablet is ejected by feed shoe.

·

77

(B)

The upper punch is adjusted to control the thickness and hardness of the tablet. A harder and thinner tablet is formed by lowering the position of the upper punch. The ejected tablets move down a vibrating wire tray or under an exhaust system to remove any loose powder. The tablets are kept in quarantine until they have been assayed and released for packaging. The wet granulation method may be summarized in the following stages: 1. The granulating solution is prepared. 2. The powdered ingredients are weighed and blended. 3. The blended ingredients are moistened by adding a proper amount of a granulating solution and kneading to the correct consistency. 4. The wet mass is passed through a sieve to form granules. 5. The granules are dried in an oven. 6. The dried granules are ground to a size appropriate for compression. 7. A lubricant and disintegrating agent are added. 8. The blended formulation is compressed into a tablet. For the developmental pharmacist, a simple lactose granulation may be a starting form ulation in which to incorporate a drug with a small dose. 18. Lactose

Starch Color Magnesium stearate Starch paste, 10%

350.00 g 26.00 g 0.25 g 5.00 g 140.00 ml

Using the geometric dilution technique, the color, starch, and lactose are uniformly mixed. The starch paste is prepared by making a slurry of the starch in a small amount of water and then adding boiling water to final volume. The starch paste should be a translucent gel. The starch paste is added to the m ixture and uniformly incorporated. The wet mass is passed through a 6-mesh sieve. The wet granulation is dried in the oven at 60°. The dried granulation is reduced to a 20- mesh to 40-mesh size,

M ·’ "J

78

·

solid phai mareuticals

depending on the desired size of the finished tablet. The granulation is mixed with the magnesium stearate ami compressed into tablets. ing/lablct 135 IQ. Calcium carbonate 100 Magnesium carbonate 50 Sodium chloride 80 Starch paste, 10% 5 Magnesium stearate 15 Dried Starch Sig.: Antacid tablet The sodium chloride, the magnesium carbonate, and the calcium carbonate are mixed until homogeneous. The starch paste is added, and the wet mass is passed through a 6-mesh sieve. The wet granules are dried in an oven at 55° for several hours. The dried granules are passed through a 14-mesh sieve. The magnesium stearate and the dried starch are added, and the mixture is tumbled until uniformly mixed. The tablets are compressed using a 13/32 in. standard concave punch and die set. Figure 42 shows the shape of some punches.

FLAT FACE

CONCAVE

G

O

O Figure 42. Shapes o f punches and tablets.

solid pharmaceuticals

20

Vitamin A. as ( lysiulets® Vitamin I)

Ascot bic acid Thiamine mononitrate Riboflavin Pyridoxine hydrochloride Cobalamin concentrate, as Stablels® Calcium panthothcnatc Niacinamide Saccharin, soluble Orange flavor, dry Mannitol Acacia Magnesium stearate Talc

·

79

5000 U.S,I’, units 1000 U.S.P. units 50.0 mg 1.0 mg 1.5 mg 1.0 mg 2 mcg 2.0 mg 10.0 mg 0.3 mg 7.0 mg 234.8 mg 6.5 mg 6.5 mg 7.0 mg

Sig.: Chewable multivitamin tablets All vitamins except vitamins A and D, ascorbic acid, and 10 per cent of the riboflavin are blended with the mannitol and acacia. The soluble saccharin is dissolved in water to make a 0.9 per cent solution, which is used to granulate the dry blended ingredients. The wet mass is passed through a 8-mesh sieve and dried at 50°. The dried granulation is passed through a 16-mesh sieve. The flavor, ascorbic acid, magnesium stearate, vitamins A and D, and remainder of the riboflavin are blended with the talc and then mixed well with the initial blend. The tablets are compressed to a hardness (see page 82) of 3 to 4 kg using a 3/8 in. standard concave punch and die set.

Precompression Method. In the precompression method of manufacturing compressed tablets, the dry

formulation is compressed into an oversized tablet or slug which is ground to a uniform size for recompression into the finished tablet. A heavy-duty tablet machine is used to make slugs 1 in. or greater in diameter. As they are to be ground, it is not necessary that the slugs be perfectly shaped. Since considerable dust may be formed, it is desirable to have the working parts of the machine housed. The precompression method is used with drugs that are decomposed by moisture and heat. In addition to circumventing the deleterious effect of moisture and heat, the precompression method saves time and labor, as it eliminates the operations of wet mixing, drying, and granulating. By eliminating water, mixtures of drugs that react in the presence of moisture may be compressed into a single tablet, e.g., the bicarbonate and acids in an effervescent tablet. All tablets cannot be made by this process. To be successful a formula must possess a reasonable adhesiveness, be moderately dense, and flow easily. Recently, spray-dried lactose has been suggested, with drugs having a small dose, as a diluent that lends itself to precompression.

21. Reserpine, 1% triturate

Lactose Sucrose Starch Magnesium stearate

mg/tablet 25.0 123.8 123.8 27.5 3.0

Sig.: Reserpine tablet, 0.25 mg

BO

·

solid pltar macent leak

Properties of Tablets The patient, the pharmacist, and the physician expect a tablet to be elegant. A speckled or unevenly colored tablet visually indicates improper and incomplete blending. In scored tablets the drug must be uniformly distributed so that the patient will receive the desired portion of the total drug in a tablet when it is divided. Any change in appearance may cause a loss of confidence in the product. Certain deterioration in tablets may be organoleptically detected. Aspirin tablets that are improperly formulated or stored produce acetic acid, which is quickly discernible. The_eye is very perceptive to a change in color, whether due to a change of the drug or the fading o f a colorant. In extreme cases, one of the drugs or a degradation product of the drug may volatilize and condense as crystals in the neck of the container. Tire above changes are easily detected, but more subtle evaluations are made before a tablet is marketed. At all times and in all products the chemical identity and purity of all ingredients in pharmaceuticals are determined by chemical analysis. The methods of analysis and control are more appropriately discussed in a text on pharmaceutical chemistry; this discussion will be concerned with the physical aspects of tablets. Dimensions. During the production of tablets frequent inspection maintains the thickness and weight within specifications. Twenty uncoated tablets are weighed individually and their average weight is calculated. To be acceptable by U.S.P. standards, the weights of not more than two of the tablets may differ from the average weight by no more than the percentage tabulated in Table XV, and no tablet may differ by more than double the percentage.

»

Influence of Compressional Force. As the granules in a tablet machine are compressed there is an increase in specific surface area as the force of compression increases. This increase in specific surface area indicates that the granules are fractured into smaller particles. In the sullathiazole table shown in Figure 43, the initial specific surface area (0.18 m2 g’ 1 ) is increased roughly five times when compressed at 1600 kg cm’2 . Bonding of the granules in the plane parallel to the direction of compression seems to be stronger than bonding in the plane normal to the direction of compression. In measuring the hardness of a tablet it is found that the tablet is harder in the parallel plane, owing to the flattening or distortion of the granules. This is obvious in the manner in which poorly formulated tablets cap or split during attempted compression. The true density of a tablet is not affected by the force of compression. The apparent density, i.e., the quotient of the weight of the tablet and its geometric volume, is a sensitive function of the force of compression. As illustrated in Figure 44, the apparent density of a tablet is proportional to the logarithm of the force. As the force of compression increases, the porosity, i.e., per cent void space, decreases. The relationship of logarithm of force to porosity is linear and has a negative slope. Porosity and apparent

Table X V

Weight-Variation Tolerances for Uncoated Tablets

Average Weight of Tablet (mg) 130 or less

Percentage Difference 10

130-324

7.5

More than 324

5

solid pharmaceuticals

·

81

jeii.Mtx .ire/‘, v C r s c Lv proportional. As shown in bigure 45. tablets seem to exhibit a maximum specific miface arc* a t a Porosity o f 10 per cent, even though the forces at which the maxima are obtained vary pom form (1*a t ’ o n < o formulation.

Figure 43. Effect of compressional force on the specific surface area of flat-faced sulfa­ thiazole tablets. [T. Higuchi, A.N. Rao, L.W. Busse, and J.V. Swintosky, J. Am. Pharm. Assoc. 42, 196 (1953).]

Figure 44. Apparent density of a spheri­ cal benzoic acid tablet is proportional to the logarithm of compressional force.

SURFACE AREA (M 2 G ')

u Figure 45. Porosity as a function of specific surface area of sul­ fadiazine and aspirin tablets. [T. Higuchi, L.N. Elowe, and L.W. Busse, J. Am. Pharm. Assoc. 43, 686 (1954).]

82

*

solid phrtnnaceuticnls

Hardness. H.ndncss is .1 icim used tu describe the resistance of tablets to mechanical weaf a $ shown in breakage and abrasion during high speed packaging and transportation. The resistance of & tablet to mechanical wear is dependent on its modulus, i.e., ratio of stress to strain, and tensile strength, i.c., breaking stress pci unit cross section, however, suitable methods of measuring the modulus of a tablet have not been developed and hardness is used as a measure of compressive tensile strength. Hardness is convenienti}' measured by the Pfizer, Stokes, or Strong Cobb hardness tester. The hardness is supposedly expressed in kilograms of force required to crush the tablet held in the jaws of the instrument used. It has been reported that a constant ratio of hardness results with the Strong Cobb tester, giving results 1.6 limes those of the Stokes tester. As shown in Figure 46, hardness is proportional to the logarithm of compressional force. In making tablets, the hardness and apparent density increase and the porosity decreases as the force of compression increases. An increase in hardness may produce a shiny and less friable tablet, but the reduction in porosity will lessen penetration of the pores of the tablet by gastrointestinal fluids, and the disintegration of the tablet will be slowed or prevented. Tablets have a hardness of/ 4 to J kg^vTroches and certain sustained-release tablets are compressed to a hardness of at least 10 kg and as great as 20 kg. Chewable tablets have a hardness of approximately 3 kg. Disintegration. The U.S.P. disintegration apparatus consists of a basket-rack assembly containing six open-ended glass tubes with a 10-mesh screen on the bottom. The basket-rack assembly is immersed in an appropriate fluid at 37° in a 1-liter beaker. The basket rack is raised and lowered through a distance of 5 to 6 cm at a rate of 30 strokes per minute. The volume of the fluid is adjusted so that the basket rack is never less than 2.5 cm below the surface of the fluid or above the bottom of the beaker. To determine disintegration time, a tablet is placed in each glass tube and a disk may be added. The disks are perforated and grooved, intended to simulate the movement of the gastro­ intestinal tract. The disintegration time is the time required for a tablet to rupture and the particles to fall through the screen or until a soft mass having no palpably firm core remains on the screen.

Figure 46. Relation of compressional force to the hardness of sulfadiazine tablets. [T. Higuchi, L.N. Elowe, and L.W. Busse, J. Am. Pharm. Assoc. 43, 687 (1954).]

FORCE (LB)

/■

solid pharm aceuticals

·

83

lhc ilixmlvp i .umn id Inbk't depends on lh