Starch

STARCH

Ann W. Newman, Ronald L. Mueller, Imre M. Vitez, Chris C.

Kiesnowski, David E. Bugay, W. Paul Findlay, Chris Rodriguez

Bristol-Myers Squibb Pharmaceutical Research Institute One Squibb Drive New Brunswick, NJ 08903

ANALYTICAL PROFILES OF DRUG SUBSTANCES AND EXCIPIENTS-VOLUME 24

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Copyright 0 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.

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CONTENTS

I. Description 1.1 Name, Formula, and Molecular Weight 1.2 Types of Starch 1.3 Appearance 1.4 General Chemical Properties 1.5 Uses and Applications 2. Method of Preparation 3. Starch Derivatives 4. Physical Properties 4.1 Structural Information 4.2 Infrared Spectroscopy 4.3 Raman Spectroscopy 4.4 Nuclear Magnetic Resonance Spectroscopy 4.5 Thermal Properties 4.6 Moisture Content 4.7 Particle Morphology 4.8 Optical Microscopy 4.9 Particle Size Measurements 4.10 Surface Area Measurements 4.1 1 Bulk Powder Properties 4.12 Hygroscopicity

5 . Methods of Analysis 5.1 Compendia1 Tests 5.2 Chromatography 6. Excipient Studies 6.1 Drng Compatibility 6.2 Tableting 6.3 Disintegration

7. References

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I. Description

1.1 Name. Formula. and Molecular Weight Starch is a polymeric material with a molecular formula of (C6H1005)n, where n ranges from 300 to 1000 [l]. Common starches contain two types of D-glucopyranose polymers called amylose and amylopectin. Amylose is a linear polymer of a-D-glucopyranosyl units linked (1-4) as shown in Figure la. These molecules can be comprised of 100 to over 1000 glucose units [2]. Amylopectin is a branched polymer of a-Dglucopyranosyl units containing (1-4) linear linkages and (1‘ 6 ) linkages at the branch points, as shown in Figure 1b. This polymer is three or more times larger than amylose [2]. Most naturally occurring starches contain approximately 30% amylose, however, specific starches and their properties are determined by the size and amount of each type of polymer molecule present in the material. The starch granules are formed by the attractive forces between the polymeric molecules. The linear portions tend to associate into micelles which bind the molecules together to form a somewhat ordered structure. Models of this structure have been proposed [3], and it is known that the structure is rigid and insoluble in water. The Chemical Abstracts identification number is CAS-9005-25-8.

1.2 T p e s of Starch Starch can be derived from a number of natural sources, including those listed in Table I. It is found in various parts of the plants and several extraction methods are used to isolate the material. The most common type of starch used in the pharmaceutical industry is corn, although studies with other forms have been performed [4-91.

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Figure 1.

Structure of (a) a linear amylose starch molecule, and (b) a branched amylopectin starch molecule.

0-

OH

r

0-

OH

OH

n

-

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Table I. Sources and Characteristics of Various Starches [ 101

Starch Type

Extracted From

Granule Shape

Granule Size (Pm)

Corn (Maize)

Seed

Round or polygonal

5 -25

Tapioca

Root

Round or oval

2 - 25

Potato

Root

Egg-shaped

15 - 100

Wheat

Seed

Round or elliptical

2 - 1 0 or 20 - 35

Sago

Stem

Oval or egg-shaped

20 - 60

Arrowroot

Root

Oval

15 - 70

Rice

Seed

Polygonal

3-8

Barley

Seed

Round or elliptical

2 - 6 or

Waxy sorghum

Seed

Round or polygonal

6-30

Sweet potato

Root

Polygonal

10 - 25

Waxy maize

Seed

Round or polygonal

5 - 25

20 - 35

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A number of starch modifications also exist and are used in pharmaceutical applications [ 11. Pregelatinized or compressible starch has been chemically or mechanically processed to rupture all or part of the granules in water. It is then dried to yield an excipient material suitable for direct-compression formulations. Sterilizable maize starch contains magnesium oxide (not greater than 2.2%) and has been chemically or physically treated to prevent gelatinization upon exposure to moisture or steam sterilization. Soluble starch results when potato or maize starch has been chemically treated to destroy the gelatinizing ability of starch. 1.3 ApDearance Starch is a fine white powder which is odorless and tasteless. It is composed of very small spherical or elliptical granules. The botanical origin of the starch material will determine the granule shape and size, and these characteristics are summarized in Table I. When the granules are analyzed microscopically, a distinct cleft called the hilum is observed, which is considered the origin of granule growth. 1.4 General Chemical Properties Starch is insoluble in alcohol, most solvents, and cold water. Alkaline solutions, however, will degrade starch and its polysaccharide components [lo]. Starch is relatively resistant to carbohydrases other than a-amylose

[ I 13. When starch is suspended in water and heated to a critical point called the gelatinization temperature, water will penetrate the granules and swell them to produce a viscous mass. With the rising temperature, the hydrogen bonds that hold the micellar structural units and the water molecules in an aggregated state tend to dissociate. The dissociated water molecules are then able to penetrate the weakened starch structure and gradually hydrate the many hydroxyl groups along the length of the starch molecule. Gelatinization temperatures vary from starch to starch, but range from 60 to75"C [lo]. Starch granules will lose their characteristic shape as gelatinization proceeds.

STARCH

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The reaction of starch with iodine is a common identity test for starch. A dilute solution of iodine stains starch a blue to bluish red color. It is believed that the amylose portion complexes with iodine by forming a helix around it [lo]. This blue color has been used both as a qualitative and quantitative test for starch in various systems. 1.5 Uses and ApD1ication.s Starch is used widely in the pharmaceutical industry because, among its other properties, it is readily available, inexpensive, white, and inert. It has been described as a tabledcapsule diluent, tablet disintegrant, and glidant [l]. The function of starch can depend on how it is incorporated into the formulation. Starch will function as a disintegrant when it is added in the dry state prior to adding a lubricant. It may exhibit both binding and disintegrant properties when it is incorporated either as a paste or dry before granulation with other agents [ 121. 2. Method of Preparation The corn kernel is made up of the tip cap, the pericarp or hull, the germ or the embryo, and the endosperm. The endosperm contains the starch granules embedded in protein cell walls. Corn kernels have two distinct regions of endosperm. The floury region in the grain center has loosely packed, rounded starch granules with a low protein content. The horny region of the endosperm at the grain edges contains angular granules with a high protein content. The granules are removed from the kernel during starch preparation. The most common preparation of starch is wet milling although dry milling is also performed [1I]. The corn is screened to remove any cob, sand or other unwanted material and aspiration is used to remove the light dust and chaff. In a process called steeping, the material is placed in a vat and the kernels are softened for milling using water, heat, and sulfur

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ANN W. NEWMAN ET AL.

dioxide. The steeped corn is coarsely ground in an attrition mill to break loose the germ which is then removed in a cyclone separator based on its density. The resulting aqueous slurry is milled a second time to release the starch granules. The kernel suspension containing starch, gluten, and fibers is passed through a concave screen to remove the fibers. The starchgluten suspension is then concentrated by centrifugation to reduce soluble material and to separate the gluten based on its density. The starch is concentrated again and washed numerous times using the cyclone separator. The starch suspension may be dried (unmodified corn starch), gelatinized and dried, or modified by chemical or physical means. After this processing. corn starch is a white powder with a pale yellow tint and bledching is required to achieve absolute whiteness. 3. Starch Derivatives Starches undergo many reactions characteristic of alcohols because of the many hydroxyl groups present in the structure. Modification of the Dglucopyranosol units can occur by oxidation, esterification, etherification, or hydrolysis. The resulting starch derivatives are defined by a number of factors such as plant source, prior treatment (acid-catalyzed hydrolysis or dextrinization), aniyloseiamylopectin ratio or content, molecular weight distribution or degree of polymerization, type of derivative (ester, ether, oxidized). nature of the substituent group. and physical form (granular, pregelatinized) [ 131.

'I he degree of substitution (DS) is a common method of characterizing starch derivatives and is a measure of the average number of hydroxyl groups on each D-glucopyranosyl unit. It is expressed as the moles of substitucnt per D-glucopyranosyl unit and the maximum DS is 3 since thrct! hydroxyl groups are available in the unit for substitution. Most conimercially produced derivatives have a DS less than 0.2. The molar substitution is used when the substituent group reacts further with the reagent to form a polymeric substituent. It is defined as the level of substitution in terms of mole of monomeric units (in the polymeric substituent) per mole of D-glucopyranosyl unit and can be larger than 3.

STARCH

53 1

Manufacture of starch derivatives includes treatment of aqueous slurries and the dry starch. For slurries, a 35-45% aqueous suspension at pH 7 to 12 and temperatures ranging up to 60°C are commonly used. Conditions are adjusted to prevent gelatinization and to allow recovery of the starch derivative in granular form by filtration or centrifugation. For dry material, the starch is treated with the required reagents by dry blending, spraying the reagents onto the starch granules or filter cake, or by suspending the starch in a reagent solution and then recovering the starch. The treated powders are then heated to temperatures up to 150°C to yield granular products with DS values up to one. Many variations on starch derivatives exist and they have been exploited in a number of ways in the food, paper, textile, and adhesive industries. More detailed discussions of starch derivatives are available [11,13,14]. Some common starch derivatives are listed below.

Hydroxyalkyl Starch Ethers such as hydroxyethyl and hydroxypropy1 Starch Phosphates such as starch monophosphates and starch phosphate diesters Cationic Starches such as the tertiary and quaternary aminoalkyl ethers Oxidized Starches made by introducing carbonyl and carboxyl groups Starch Acetates Cross-Linked Starches Acid-Modijied Starches 4. Physical Properties

The physical properties of unmodified and pregelatinized corn starch from three vendors were characterized and the materials analyzed are summarized in Table 11. Examples of unmodified corn starch are STA-Rx and Purity 2 1. Starch 1500 is a sample of partially pregelatinized starch and Starch 1551 represents fully pregelatinized starch. Starch 1500 LM is a partially pregelatinized starch with a low moisture content.

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Table 11. Starch Materials Analyzed for Physical Properties

Starch Type

Vendor

Trade Name

Total Volatile Content (%)

tinmodified corn

Staley

STA-Rx

10.9

Unmodified Corn

National

Purity 21

10.2

Pregelatinized

National

1551

8.3

Pregelatinized

Colorcon

1500

9.4

PregelatinizedLow Moisture

Colorcon

1500 LM

6.5

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4.1 Structural Information Starch is a semicrystalline polymer. The linear amylose molecules are amorphous in nature, but the branched amylopectin portion has been reported as partially crystalline. It is believed that the crystalline regions in the starch granule are interspersed in a continuous amorphous phase [3,13,15]. X-ray diffraction studies have shown that starch exists in three crystal forms designated A, B, and C. These forms are dependent on the botanical source of the starch. Pattern A is observed for cereal grain starches, whereas pattern B is characteristic of tuber, fruit, and stem starches. Pattern C is intermediate between the A and B patterns and has been attributed to mixtures of A and B type crystallites [151. The A type pattern is commonly observed for corn starch. Single crystal x-ray diffraction data for the crystalline portion of A type starch has been reported [16], and it was found to crystallize in a monoclinic lattice with a = 2.124 nm, b= 1.172 nm, c=l.069 nm and y=123.5 '. The unit cell contains 12 glucose residues located in two lefthanded, parallel-stranded double helices packed in a parallel fashion. Four water molecules are located between these helices. Intramolecular hydrogen bonding was not observed and the interstrand stabilization in the type hydrogen bonds. double helix is attributed to O(2)...0(6) It has been reported that the B type starch also contains chains arranged in double helices [ 171. The currently accepted hexagonal unit cell has dimensions of a=b=l.85 nm and c= 1.04 nm. The A and B structures differ in crystal packing of the chains and in moisture content. Powder x-ray diffraction patterns for representative unmodified and pregelatinized corn starches are given in Figure 2. The unmodified corn starch was found to have some crystalline character as evidenced by the broad peaks present. The pattern is indicative of a semicrystalline material and is similar to the A type pattern, but a definite determination of the form is difficult based on the quality of the pattern. The pregelatinized

ANN W. NEWMAN ET AL.

534

X-ray powder diffraction patterns of unmodified (upper trace) and pregelatinized (lower trace) corn starch

Figure 2.

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Ln N

Q

N

v)

r(

0

rl

Ln

1

1

m - m m ~ Q + Q D N f r l

1

1

m m 9

rl

1

1

m f

rl

1

~

1

Q

N

rl

1

m

1

Q

m

4

1

1

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1

1

Q

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9

1

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m r 1p

1

1

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n

N

1

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m s Q

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STARCH

535

Starch 1551 material exhibits a broad amorphous halo in the powder pattern indicating that the majority of the sample is amorphous material. This type of pattern was expected since the processing of pregelatinized starch destroys the crystalline portions of the granule. 4.2 Infrared Spectroscopy Diffuse reflectance (DR) infrared (IR) spectra were acquired for unmodified, partially pregelatinized, fully pregelatinized, and partially pregelatinized (low moisture) corn starch. Identical IR spectra were measured for the unmodified, partially pregelatinized, and fully pregelatinized starch samples and are represented in Figure 3. The partially pregelatinized (low moisture) starch sample displayed slight shifts in the absorbance bands assigned to the glycosidic COC and coupled CO stretch vibrational modes. The IR spectral band assignments are presented in Table I11 [IS]. The measured absorbance bands are consistent with the structure of starch. 4.3 Raman Spectroscopy Raman spectra were acquired for unmodified, partially pregelatinized, fully pregelatinized, and partially pregelatinized (low moisture) corn starch. Identical Raman spectra were measured for the unmodified, partially pregelatinized, and fully pregelatinized starch samples and are represented in Figure 4. The Raman spectral band assignments are presented in Table IV [191. The measured absorbance bands are consistent with the structure of starch. 4.4 Nuclear Magnetic Resonance Spectroscopv Solid-state 13Ccross polarizatiodmagic angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectra were acquired for unmodified, partially pregelatinized, fully pregelatinized, and partially pregelatinized (low moisture) corn starch. Identical I3C spectra were measured for each and are represented in Figure 5.

5%

Figure 3

ANN W. NEWMAN ET AL.

Infrared spectra of ( a ) unmodified corn starch, STA-Rx, (b) partially pregelatinized corn starch, Starch 1500, (c) fully pregelatinized corn starch, Starch 1551, and (d) partially pregelatinized corn starch with low moisture content, Starch 1500 LM

T

i

STARCH

Table 111. Diffuse Reflectance IR Spectral Assignments Wavenumber fern-')

Structural Assignment

-3350

OH stretch

2929,2898

CH stretch

1452

CH, bend

1417,1335, 1302

CH bend

1364,1240,1206

OH in-plane bend

1148 (1 166 for LM starch)

glycosidic COC asymmetric stretch

1076 (1065 for LM starch), 1012

coupled CO stretch, CC stretch, and OH bend

930

ring vibration

862

C,-group vibration

764

ring breathing vibration

709,643,606,576,524

low frequency ring vibrations

537

538

Figure 4.

ANN W. NEWMAN ET AL.

Raman spectra of (a) unmodified corn starch, STA-Rx, (b) partially pregelatinized corn starch, Starch 1500, (c) fully pregelatinized corn starch, Starch 1551, and (d) partially pregelatinized corn starch with low moisture content, Starch 1500 LM.

STARCH

Table IV. Raman Spectral Assignments Raman shift (cm-')

Structural Assignment

-3365

OH stretch

2932,2907

CH stretch

1459

CH,, CH, deformation

1380

CH, symmetric deformation

1335

CH deformation (?)

1123,1081,1051

CC stretch

938,855,577,479,440

ring and lattice vibrations

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540

Figure 5 .

Solid-state 13CCP/MAS nuclear magnetic resonance spectra of (a) unmodified corn starch, STA-Rx, (b) partially pregelatinized corn starch, Starch 1500, (c) fully pregelatinized corn starch, Starch 1551, and (d) partially pregelatinized corn starch with low moisture content, Starch 1500 LM.

c

c

STARCH

54 1

Table V. Solid-state I3CNMR Spectral Assignment

NMR Chemical Shift (ppm)

Structural Assignment"

61.9

C6

72.2

c4

81.5

C2, C3, and C5

101.2

c1

~~

"Carbon numbering scheme based upon Figure 6.

Figure 6.

13

Numbering system of the starch sub-unit used for the CNMR assignments.

OH

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ANN W. NEWMAN ET AL

The resonance positions and structural assignments for the solid-state 13C NMR spectrum of starch are presented in Table V. Although the CP/MAS technique provides a “liquid-like” NMR spectrum, the broad nature of the carbon resonances prevented spectral resolution of all the carbon signals at a Larmor frequency of 62.89 MHZ. Solution-phase, ‘H NMR studies in DMSO-d, have also been performed on amylose and model compounds 1201. Spectral assignments and intramolecular hydrogen bonding suggest that the same conformation is perpetuated along the amylose chain. 4.5 Thermal Properties Thermal analysis has also been used to characterize the structure of starch. A melting endotherm due to the crystalline portions of starch has been studied [21], but it is not clearly resolved in all samples due to the small amount of crystalline material present in the samples. The transition is also dependent on the sample preparation and moisture content of the material. The melting point of starch has been calculated using an equation developed by Florey [22] for polymeric systems. Using this approach, the melting point of the pure polymer has been reported as 168“C [2 11. Using the same equation and hot stage data, a melting point of 210°C has also been reported [23,24]. The glass transition and gelatinization temperatures have also been studied for starch materials [25,26]. Studies of the glass transition in wheat starch have been performed using differential scanning calorimetry (DSC) [25]. This thermal event was found to be dependent on the moisture content of the preparation and was ill-defined below 13% moisture. When observed, it occurred at approximately 40°C. The onset of melting was also dependent on the moisture content of the samples in this study and was found to range from approximately 60 to 80°C. Gelatinization studies of starch have also used DSC [26]. Concentrated starcWwater suspensions produced a well-defined endotherm under suitable conditions which could then be integrated to obtain the heat of gelatinization for various starches.

STARCH

543

A representative DSC curve collected for corn starch with a low moisture content (9%) is given in Figure 7. The sample was analyzed as received in a hermetically sealed pan with a pinhole to allow for controlled pressure release. A broad endotherm is observed for the sample over a temperature range of 50-150°C. The thermogravimetric (TG) curve in the overlay shows a weight loss in the same temperature range as the endothermic transition, therefore, it was designated as a dehydration. A similar curve was also observed for the pregelatinized starch samples. The glass transition for the sample was not expected to be clear due to the low moisture content of the samples. The dehydration predominated with the sample preparation used and the melt endotherm was not observed for the corn starch sample.

To obtain information on the glass transition in pregelatinized starch, a sample was equilibrated in a 90% relative humidity chamber for 19 days. The volatile content of the sample was 17% after equilibration. The sample was then placed in a hermetically sealed pan and analyzed. The glass transition was evident at approximately 53 "C, as shown in Figure 8. It is evident that the sample preparation is a critical factor in obtaining specific information using DSC. 4.6 Moisture Content The moisture content of starch has been determined using a number of techniques including Karl Fisher measurements [27], thermogravimetry (TG) [28], loss on drying (LOD) [l], and NMR spectroscopy [28]. The National Formulary (NF) and British Pharmacopeia (BP) specify that moisture contents should be less than 14, 15, or 20%, depending on the botanical source of the material. The moisture contents of the commercial corn starch lots were measured using TG analysis and are given in Table 11. The unmodified corn starch samples had moisture levels around 1O%, which is similar to that reported for similar types of samples [13. The amount of water in the pregelatinized samples was slightly lower than that of the unmodified corn starch samples, ranging fiom approximately 8 to 9%. The low moisture

ANN W. NEWMAN ETAL

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Differential scanning calorimetry thermogram (lower trace) and thermogravimetry profile (upper trace) of unmodified corn starch.

Figure 7.

9

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In

4

9 r

a Y

n U

3 Y

i?

r

0

P

10G

-

2;

3

E n

O

E

:+

. 10 I

0 10

I

N 10

0

STARCH

545

Differential scanning calorimetry thermogram of pregelatinized starch showing the glass transition.

Figure 8.

0 m r

m

t

v) N

/ *

I

9

0

m

0

I

0

I

?J 9

‘y

5Jh

ANN W. NEWMAN ET AL.

pregelatinized starch did exhibit a significantly lower moisture content of 6.5%. 4.7 Particle MorpholoFy A number of excellent reviews on the microscopy of starches have been published [ 10, 29-32]. Areas covered in these references include granule morphology, granule size, gelatinization temperatures, and staining. Our discussion will focus on granule morphology using scanning electron microscopy.

As summarized in Table I for a number of starches, the granule shape and size is characteristic of the botanical origin and can be used to identify the materials. It has been reported that the floury granules, as found for potato and tapioca starches, tend to be larger and more regular in shape. Descriptive terms used for these types of granules include round, elliptical, or oval. Horny starches, such corn and rice, are usually described as polygonal because of the angular sides of the granules caused by the close packing of the granules in the kernel. Starches are found as individual granules, but aggregated materials are also observed and are attributed to the drying conditions. Extensive heat and moisture during drying will produce a slight gelatinization of the surface of the granule and cause the granules to adhere together to form the aggregates.

Electron microscopy has been useful in the morphological study of starch grunules 133-351. Scanning electron microscopy (SEM) exhibits good depth of field and gives detailed information about the surface of dry granules. The low magnification SEM micrograph in Figure 9a shows the uniform particle size and shape for STA-Ku. The polygonal and round shape of' the unmodified corn starch is illustrated in Figure 9b at a higher magnification. The surfaces of the granules are relatively smooth and pores are not evident at this magnification. An aggregate showing some fusion of the granulc surfaces of unmodified corn starch is shown in Figure 1 0. The pregelatinized starch sample exhibits an entirely different morphology, as shown in Figure 1 1. The particles are irregular and show large pores for the majority of particles. The pregelatinization process has

STARCH

Figure 9a. Scanning electron micrograph of unmodified corn starch granules, taken at a magnification of 270x.

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ANN W. NEWMAN ET AL.

Figure 9b. Scanning electron micrograph of unmodified corn starch granules, taken at a magnification of 2700x.

STARCH

549

Figure 10. Scanning electron micrograph of an aggregate found in an unmoMied corn starch sample, taken at a magnification of 1500~.

SS(1

ANN W. NEWMAN ET AL

Figure 1 1. Scanning electron micrograph of pregelatinized Starch 155 1, taken at a magnification of I OOx.

STARCH

55 1

ruptured the granules resulting in a new particle morphology. SEM has also been used to investigate the properties of starch in a tablet [36]. It was found that starch possessed elastic properties during compression, with maize and rice starch being more elastic than potato. As the applied pressure was increased, deformation of the starch granules was reported and could predominate at very high pressures. It was also concluded that starch particles do not fuse together and were nearly always surrounded by a space which contributed to the disintegration properties.

4.8Optical Microscopv Optical microscopy has been a powerful tool in the study of starch materials and common starches have been readily identified using this technique. It has been suggested that starch be examined as a 0.2-0.3% suspension in water or glycerol to obtain the best images [30,3 11. A polarizing microscope also gives information about the starch granules. When unmodified starch granules are observed using polarized light, two dark lines intersecting at the hilum will form a cross or a V-shape. The shape of the cross can be used to help identify the type of starch. One explanation for this feature suggests that the density and distribution of moisture throughout the granule are not uniform and the hilum contains more moisture than the other regions [lo]. As the granules dry,stresses are formed within the granule resulting in the bright regions observed under the polarized light. When the starch swells or is gelatinized, the cross is no longer visible with the polarizing microscope [32]. The absence of this cross is a simple and accurate determination of the presence of gelatinized granules in a starch sample. An example of an unmodified corn starch suspended in water is given in Figure 12a. The polygonal and round shape is evident for the granules, but less detail is obtained when compared to the SEM micrographs. The sample was also analyzed under crossed polarizers, and the crosses are clearly observed for the granules, as shown in Figure 12b. When partially pregelatinized starch 1500 is suspended in water and observed under the optical microscope, very few details of the particles are discerned, as

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ANN W. NEWMAN E T A L

Figure 12a Optical micrograph of unmodified corn starch, using ordinary illumination at a magnification of 400x

STARCH

553

Figure 12b. Optical micrograph of unmodified corn starch, using crossed polarizers at a magnification of 400x.

55-1

Figure 13,

ANN W. NEWMAN ETAL.

Optical micrograph of pregelatinized Starch 1500, obtained using ordinary illumination at a magnification of 200x.

STARCH

555

Figure 13b. Optical micrograph of pregelatinized Starch 1500, obtained using crossed polarizers at a magnification of 200x.

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ANN W. NEWMAN ET AL.

shown in Figure 13a. The transparency of the particles is due to the refractive index similarities between the sample and the solvent. The irregular shape of the particles is evident, however, and a few intact granules may be present. Figure 13b is a micrograph of this sample under crossed polarizers. It is evident that the majority of the sample was pregelatinized, however, some intact granules exhibiting crosses are also visible in the lower left quadrant. 4.9 Particle Size Measurements

Particle size can affect the disintegration, flow, handling, and tableting properties of these materials. Sieving is a common method for obtaining specific size fractions for granulation and disintegration studies [37-401. Other studies characterize the particle size distribution of the materials as received from the vendors to investigate possible variations in the properties of the excipient. A wide range of granule sizes, spanning from 2 to 150 pm, has been reported for various starches [lo]. The size of the granule is generally expressed as the length of its longest axis in microns [3 11. The results of a number of measurements can be expressed either as a range or as an average size. Starches such as rice show a relatively uniform distribution, therefore, an average size is appropriate. Other starches, such as maize, show a wide distribution of sizes and a range would more accurately describe the granule size. Rye and wheat starches are known to exhibit bimodal distributions of very large and very small granules. A number of methods for determining the particle size of various starches have been used. For bulk powder analysis, sieving is employed for large amounts of material [ 13. One of the most common methods for particle size determination is optical microscopy 141,423 because it gives a direct measurement of the individual particles. Automated systems have been used to examine the particle sizes of starch materials with good results [43,44]. Laser light scattering analysis has also been utilized to measure the size of dry particles (particles in air) and suspensions (particles in liquid) [45]. This technique is suitable in many cases, but since it is not a

STARCH

557

direct measure of the particles, the data was checked using SEM. It was concluded that laser light scattering analysis was dependent on the model used to fit the data and better reproducibility was obtained with samples suspended in liquid. The particle size distributions of starch samples from the various vendors were collected using optical microscopy and an image analysis system. This type of measurement was suitable for the fine particles in the sample but large aggregates would not have been included. The mean particle sizes are summarized in Table VI. A measure of 95% of the particles is also given in Table VI to assess the number of large particles in the sample. The mean particle size exists in a narrow range from 5.7 x 9.4 to 12.8 x 18.9pm. The different processing of the various starches does not appear to have substantially changed the mean particle size of the fines. The distributions are shown graphically in Figure 14 for the particle length range 0-30 pm since this range included most of the particles measured. The distribution of the particle length is similar for the five starch samples, with the majority of the particles having a length between 4 and 20 pm. STA-Rx and Starch 1551 appear to have more particles in the range 2 to 10 pm, whereas Starch 1500 and 1500 LM appear to have more particles in the 10 to 20 pm range. 4.10 Surface Area Measurements Surface area measurements of starches have been obtained by air permeametry [9,39] or nitrogen adsorption [46]. Relatively low surface areas ranging from approximately 0.1 to 0.5 m2/ghave been reported [9], however, values as high as 3 m2/ghave also been observed [46]. Surface area measurements on unmodified and pregelatinized corn starch samples were obtained using a five-point nitrogen BET analysis after outgassing the samples at room temperature under vacuum. The values are listed in Table VI. The surface areas range from 0.18 to 0.36 m2/g which is in agreement with literature values reported for similar materials. The low surface areas can be partially explained by the low porosity of the materials as seen in the SEM photos.

ANN W. NEWMAN ET AL.

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Table VI. Particle Size and Surface Area Data for Starch Lots

Starch Type

Mean Particle Size (pm)

95% Less-Than Value (pm> *

Surface Area (m2/g)

STA-RX

8.4 x 11.1

17.3 x 22.6

0.35

Purity 21

10.6 x 15.0

25.4 x 35.7

0.36

1551

5.7 x 9.4

15.1 x 24.7

0.18

1500

12.8 x 18.9

31.1 x 46.2

0.26

1500 LM

10.1 x 14.8

19.6 x 28.9

0.24

*

Particle size for which 95% of the measured particles were smaller than.

Figure 14.

STARCH

Particle size distribution of commercial starches.

0'2-82

8Z-92

PZ-ZZ

zz-oz OZ-81 81-91

91-91

P 1-2 1

ZL-01 01-8

8-9 9-P P-Z

559

560

ANN W. NEWMAN ET AL.

4.1 1 Bulk Powder Properties Bulk powder properties are important in understanding the handling properties of an excipient or a granulated product. A number of studies have investigated the bulk powder properties of starch [9,42,47] and granulations made with starch [6,12,48]. Common parameters measured are bulk and tap density. From these values the compressibility can be calculated using the following equation: 100 x

(tap density - bulk density)

tap density

= %

compressibility

(1)

A classification system to evaluate the flow properties of powders has been introduced by Can: [49,50]. A flowable powder is defined as freeflowing and will tend to flow steadily and consistently, whereas, a floodable powder will exhibit an unstable, discontinuous, and gushing type of flow. The parameters in Carr's system include angle of repose, angle of spatula, compressibility, cohesion, and dispersibility. Based on these parameters, flowability and floodability indices are calculated to determine the handling properties of bulk solids.

Various starches have been characterized using C a d s system and the Hosokawa powder characteristics tester [47]. To compare the bulk powder properties of unmodified and pregelatinized corn starches from the various vendors, the same instrumentation and procedures were used. The results are summarized in Table VII. The parameters used to obtain the flowability index are compressibility (from bulk and tap density), angle of repose, and angle of spatula. The values obtained for these tests were similar to those previously reported for similar materials [47]. The flowability indices of 3 1 and 36 for the two unmodified starches are similar and indicate the materials to be very

STARCH

56 1

poorly flowing powders. The pregelatinized starches exhibited flowability indices in a narrow range of 52-54 indicating that these materials would also have poor flow properties. The floodability indices were evaluated using the angle of fall, angle of difference, and dispersibility measurements. The floodability indices for all five starches ranged from 62 to 86. Values in this range are indicative of floodable material which will exhibit difficult handling properties for the bulk powder. Previous data on similar materials reported poor to borderline flow characteristics using this system [47]. The mass flow rate data are also given in Table VII for comparison. The relatively low mass flow rates ranging from 0.04 to 1.OO g/sec demonstrate the poor flow properties of these materials. The unmodified starch samples exhibited the lowest flowability indices and the lowest mass flow rates. The small particle size is largely responsible for the floodable properties of these materials. 4.12 Hygroscopicity Starch has been classified as a moderately hygroscopic material [5 13. Water sorption studies have been conducted using static methods (saturated salt solutions in closed chambers) [5 1-53], modified inverse frontal gas chromatography [54], as well as other techniques [27,55]. The isotherms are typically type I1 curves exhibiting hysteresis (an amount of sorbed moisture remaining during desorption) [5 11. Hysteresis is usually attributed to ink bottle pores in which the water cannot escape the pore due to the constricted neck. In the case of starch, the hysteresis has been attributed to intra- and intermolecular hydrogen bonding of water with the hydroxyl groups of the starch molecule [51,55,56]. The extent of hydration and swelling depends on the accessibility of the hydroxyl groups in the starch to the water [55]. It has been suggested that the amorphous regions are responsible for the reversible swelling of starch upon the adsorption of water [131.

ANN W. NEWMAN ET AL.

S62

Table VII. Bulk Powder Data for Starch Lots

Property

STA-Rx

Purity 21

Starch 1551

Starch 1500

Starch 1500 LM

1.54

1.54

1.55

1.54

Bulk density (g/mL)

0.46

0.55

0.46

0.60

0.63

Tap density (gimL)

0.79

0.83

0.65

0.87

0.86

Compressiblity

42

34

30

31

27

Angle of Repose (deg.)

62

62

43

36

41

Angle of Spatula (deg.)

84

77

64

72

63

Dispersibility

7

6

8

6

4

Cohesion

4

5

15

12

12

Angle of Fall (deg.)

48

54

28

28

25

(3.)

563

STARCH

Table VII. Bulk Powder Data for Starch Lots (continued)

Property

STA-Rx

Purity21

Starch 1551

Starch 1500

Starch 1500 LM

Angle of Difference (deg.1

14

8

15

9

16

Flowability Index

31

36

52

54

53

Flowability performance

very poor

verypoor

poor

poor

poor

Floodability Index

68

62

72

72

86

Floodability performance

floodable floodable

Mass Flow Rate (g/sec)

0.04

0.06

floodable floodable

very floodable

0.53

1.oo

0.83

ANN W. NEWMAN ET AL.

.%-I

The amount of water sorbed by a solid can be expressed in a number of' ways. Many investigators report the amount of water sorbed, but the amount of water initially in the sample is not taken into account. The calculation of percent uptake relative to the dry weight of the sample normalizes samples to the same initial point and makes data from various samples comparable. The percent sorbed relative to dry weight is calculated from equation 2.

where:

W, = weight of sample at equilibration W, = original weight of sample A = percent moisture in original sample

A second method of reporting data is the equilibrium moisture content (EMC) [ 1,571 which is calculated using the following equation:

EMC

=

P

+

100

x 100

where [ Wo x

P =

wo -

1- A

100

P o x

*B 1-

A

X I

00

(4)

100

B = weight change at equilibrium 'The hygroscopicity of the commercial starches was investigated with an automated moisture balance system in the range 0 to 90% RH [%I. EMC sorption values were calculated from the raw data at each relative

STARCH

565

humidity and are summarized in Table VIII. Representative curves are given in Figures 15 and 16. The sorption curves for the various starch samples are similar. The Type I1 isotherm and the hysteresis are evident for all the samples and the weight percent sorbed at 90%RH is fairly consistent at about 20%. The unmodified corn starch data are shown in Figure 15 for the Purity 2 1 sample. It is apparent that unmodified corn starch readily sorbs moisture along the entire range up to 90%RH. The isotherm for the pregelatinized starch in Figure 16 is similar, but the magnitude of the hysteresis is larger in the range 30-80%RH. These sorption curves are in agreement with data reported for similar types of samples [ 11. 5. Methods of Analysis 5.1 Compendia1 Tests The National Formulary [59] contains the following assays for starch: Botanic characteristics: Corn starch is described as polygonal, rounded, or spheroidal granules up to about 35 pm in size and usually having a circular or several rayed central cleft. Identification: A smooth mixture of starch and cold water is made. Boiling water is added and the mixture is boiled gently for 2 minutes. When the product is cooled, the product is a translucent, whitish jelly. In a second test, a water slurry is colored reddish violet to deep blue by iodine test solution (TS). Microbial limits: Following test method <61>, the sample meets the requirements for the absence of Salmonella species and Escherichia coli. pH: A slurry of starch and water is prepared in a nonmetallic container and agitated continuously for 5 minutes. The pH is measured immediately to the nearest 0.1 unit. For corn starch, a

566

Figure 15

ANN W. NEWMAN ET AL.

Moisture isotherm for unmodified corn starch, purity 2 1 .

0 - m 0

Figure 16. 1551.

STARCH

Moisture isotherm for pregelatinized corn starch, Starch ~.

5 67

ANN W.NEWMAN ET AL.

568

Table VIII. Sorption EMC Values at Various Relative Humidities

Relative Humidity

STA-Rx

Purity 21

Starch 1551

Starch 1500

Starch 1500 LM

1

3.4

4.4

3.6

3.5

3.6

10

6.0

6.3

5.6

5.4

5.4

20

8.1

8.3

7.3

7.5

6.9

30

9.5

9.6

8.6

9.0

7.9

40

10.7

10.8

9.7

10.1

9.1

50

11.9

11.9

10.8

11.2

10.7

60

13.1

13.2

12.2

12.1

12.3

70

14.6

14.9

14.1

13.2

14.1

80

16.8

16.9

16.8

15.5

16.2

90

19.9

20.1

21.5

19.2

20.5

(%I

STARCH

569

value between 4.5 and 7.0 should be obtained.

Loss on drying: Following the general test method <73 1>, the sample is dried at 120°C for 4 hours. It should not lose more than 14.0% of its weight. Residue on ignition: Following test method <281>, the weight of the residue can not exceed 0.5% on a 2 g sample. Iron: The residue obtained in the test for Residue on ignition is dissolved in hydrochloric acid with gentle heating, diluted with water, and mixed. This sample is diluted with water and tested for iron according to test <241>. The limit is 0.002%. Oxidizing substances: Starch and water are swirled for 5 minutes and decanted into a centrifuge tube. It is centrifuged to clarify. The clear supernatant is transferred and glacial acetic acid and potassium iodide are added. The sample is swirled and allowed to stand in the dark for 25-30 minutes. Starch TS is added and the solution is titrated with sodium thiosulfate volumetric solution (VS) until the starch-iodine color disappears. Not more than 1.4 mL of sodium thiosulfate is required. Sulfur dioxide: Starch and water are mixed until a smooth suspension is obtained. The solution is filtered. Starch TS is added to the clear filtrate and the solution is titrated with iodine to the first permanent blue color. Not more than 2.7 mL is consumed. Organic volatile impurities: The sample should meet the requirements for Method N in general test <467>.

5.2 Chromatomaphv High-pressure liquid chromatography (HPLC) methods have been used by the food [60] and paper [61] industries to analyze for starch. One method uses acid hydrolysis of the starch to detect glucose as the starch

570

ANN W. NEWMAN ET AL.

degradation product [60]. Good agreement was obtained with titrimetric data. A second method converts the starch to dextrose using enzymes and subsequent HPLC analysis [61]. The chromatographic method was found to be more reproducible than a spectrophotometric method in quantifying starch. 6. Excipient Studies

6.1 Drug Compatibilitv Starch is a relatively inert material and interactions with active drug substances do not occur often. Excipient compatibility studies of starch and various active drugs have been performed using thermal methods of analysis. As an example, starch has been found to be compatible with erythromycin [62], cephalexin [63], and acetylcysteine [64] using this method of excipient screening. 6.2 Tableting Various properties of starch have been studied to better understand its role in the granulation and compaction processes. It has been reported that starches deform mostly by plastic flow, but this was found to be dependent on the particle size, size distribution, and particle shape [38]. Characterization of wet granulated formulations made with starches from various vendors have shown no physical differences, yet, the compaction and ejection forces were found to be different for the formulations [48]. The effect of heat formation during compression has also been investigated for various starches and excipients [65,66]. The effect of the binder and tablet geometry have been related to the hardness and tensile strength of starch tablets [67]. Studies have shown that the particle size of an excipient may also affect various tablet properties [38,39,41,68]. A decrease in the particle size of compressible starch has resulted in a decrease [68] and an increase [38] in tablet strengths.

STARCH

57 1

The tabletting properties of starch in various formulations with active drug substances have also been reported [4,37,69]. Various starches (maize, rice, potato, wheat) were studied for use in double compressed tablets of aspirin and it was found that corn starch exhibited the best disintegration properties while rice exhibited the worst [4]. The compression speed used to tablet aspirin and compressible starch showed weaker and more porous tablets at high compression speeds [37]. A comparison of compressible starch with regular starch in an aspirin formulation resulted in better flow and compressibility properties for the compressible starch, as expected from the properties of the two materials [69]. 6.3 Disintegation As discussed previously, starch is used in many formulations for its disintegrationproperties. The mechanism for the disintegration properties of starch has been studied and various conclusions have been published [70-731. The most common explanation for the disintegration properties is the swelling of the starch granules when exposed to water and it has been proposed that amylose is the component responsible for the disintegration properties of starch due to swelling [69]. Measurements of the granules to quantify the amount of swelling have been performed using various methods [56,74]. A second mechanism was proposed that suggested the disintegrating action of starch in tablets is due to capillary action rather than swelling [70]. A third mechanism has been proposed based on the particle-particle repulsion forces between the tablet constituents when in contact with water and the hydrophilic nature of starch [72].

When comparing various starches as tablet adjuvants, it was found that disintegration time for the tablets was independent of the compressional force, but was dependent on the type of starch [5,42] and the dissolution method [5]. A study of compression forces showed that starch tablets had a decrease in disintegration with an increase in tablet hardness [73]. Particle size has also been correlated with the disintegration times of tablets containing starch [39], and it has been suggested that tight controls on particle size can minimize batch failures [44].

ANN W. NEWMAN ET AL.

572

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2.

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32.

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33.

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