Triaxial Compression of “Cappable” Formulations

Triaxial Compression of “Cappable” Formulations J. T. CARSTENSEN*, G. J. ALCORN*,S. A. HUSSAIN~, AND M. A. ZOGLIO*’ Received February 2, 1985, from the ‘School of Pharmacy, Universi of Wisconsin, Madison, WI 53716; *Merrell Dow Research lnstitufe, Cincinnati, OH 45215; and the 5College of Pharmacy, University of 8ncinnati, Cincinnati, OH 45267. Accepted for publication July 25, 1985. prone to capping, the values of H(A) and H(B) (see Fig. 1) are sufficiently high (e.g., above 20 kg hardness on a Schleuniger hardness tester) to allow packaging and transportation without breakage and capping. In many reported cases,“ the response is linear (OA; see Fig. 1);i.e., capping is quite remote, whereas in some cases,4 curvature (OBI but no maximum is observed in a practical range of applied compressional force P(B). In the latter case there may be occaThe problem of “capping” and lamination is associated sional tablets that cap in a product, but the product is not with the compression of several well-known drug substances and their granulations and mixtures. Examples are N-acetylconsidered to be capable. This term is reserved for product which shows a maximum (OCD) in the hardness applied force p-aminophenol and ibuprofen.’ Hiestand*S2showed in a series of elegant experiments that curve. the problem of “capping” (visible lamination) is to a large This report describes a method of applying the Hiestand degree associated with uniaxial relaxation in the tablet die principle to a product which is prone to capping and in this at the pointe morte, i.e., the point a t which the upper punch fashion producing a “noncapping” product. The principle (Fig. 2) is to compress the problem formulation on a compresforce is released. Some capping may also occur at ejection, as sion coating machine. The first stage of compression (the demonstrated by Rue et aL3and, in the case of erythromycin “inner” tablet) is carried out at a pressure below P* (which base, by Hiestand.’ makes a tablet which is insufficiently hard for packing and In the work of Amidon et a1.,2 decompression occurred shipping). The second-stage material for what is usually the simultaneously in all directions, thereby relieving a t least outer coat is a material with a high elastic limit (E*). The some of the die wall pressure during the decompression second compression is carried out a t a compressional presprocess. Capping problems were reduced and, in some cases, sure below the elastic limit, so that the outer granulation eliminated by this simultaneous triaxial decompression. only deforms but never bonds. The inner tablet experiences An essential part of theory, therefore, is that uniaxial the second compression pressure triaxially, and decompresrelaxation causes capping. In general, a hardness versus sion is also three dimensional, because the outer granulation applied force profile has the appearance shown in Fig. 1.P* is the maximum practical pressure applicable to the p r ~ d u c t . ~ never bonds and hence simply decompresses into the original particles. The inner tablets should therefore be harder and At this point, the maximum practical hardness, H*, is not cap if the Hiestand theory is correct. achieved. At higher pressures, the hardness will decrease due to lamination. When a product or granulation is not

Abstract 0According to theory, “capping”(visiblelamination)occurs at the uniaxial relaxation stage at the point at which the upper punch pressure is released. A method is described whereby the stress in a tablet prone to a “capping”problem can be released in a triaxial manner.

Experimental Section Probucol is a substance which has a profound tendency to cap. Attempts can be made to produce 250-mg tablets on a single punch tablet machine with a starch-microcrystalline cellulose-hydroxypropyl methylcellulose formulation on a 7/16-inch standard concave punch, using a tablet weight of 290 mg. If the pressure is such that the tablets are 4-5 kg hardness, then capping becomes noticeable and H* (Fig. 1)is about 5.5 kg Schleuniger hardness for this product. On a rotary tablet press, H* is about 4.5 kg Schleuniger hardness. It therefore constitutes a cappable product. Tablets were produced on a single punch tablet machine with the characteristics shown in Table I. These were then to be placed in a bed of a non-compressible material. Polyethyloxazoline (The Dow Chemical Co., Midland, MI) was lubricated with 3% magnesium

In In Y

z n

a U

I P < P’

0

P < E‘

P+

pB APPLIED FORCE OR APPLIED

PRESSURE a

Figure 1-Typical hardness versus applied pressure plots. Key: (OA) good product; (08)product; (OB) product with occasional cappers; (OCD) cappable product. 0022-3549/85/1100-1239$0 1 .OO/O 0 1985, American Pharmaceutical Association

b

Figure 2- (a) Compression of inner tablet; (b) positioning of inner tablet in polymer bed; (c) double compression. Journal of Pharmaceutical Sciences / 1239 Vol. 74, No. 1 1 , November 1985

Table I-Physical Characteristics of Inner Tablets Made by Simple One-Step Compression

Group

Compression Pressure, Kp

Hardness, kga

Friability, %

Thickness, cm a

Diameter, cm

A B

1.3 1.6 4.6

1.5 ? 0.5 4.0 +- 0.3 5.6 f 0.5

3 1.2 1.1

0.554 t 0.006 0.528t 0.005 0.516 2 0.006

1.12 1.12 1.12

C*

Results are the mean & SD of five determinations. bGroupC contained a large number of capped tablets. Only noncapped tablets were used for the physical measurements. stearate and found to be non-compressible at pressures up to 8 tons force on a Carver Press when a 518-inch punch was used. This material was used for the outer coat, and the inner tablet was compressed i n a bed of the polymer on a 518-inch punch (Fig. 2b and c). The tablet and polyethyloxazole granules were then ejected and collected in a drum, and the tablets were separated from the polymer by passage through a 10-mesh sieve. The polymer granules can be reused. The compressional forces used in the second compression are listed in Table 11,as are the hardness of the final tablets. The friability and the dimensions of the tablets are also shown. To determine what the effect would be by precompression, the following experiments were carried out. Tablets were made on a hydraulic press (F. Carver, Menomonee Falls, WI) by first applying the pressure indicated in the second column of Table I11 and then applying compression a t a force such as that listed in the third column of the table.

Results and Discussion It is noted from Table I11 that the capping tendencies of probucol tablets could not be alleviated by precompression. In fact, in some cases the precompression seemed to aggre-

vate the problem; e.g., in the case of the tablets precompressed a t 1.2 Kp and compressed at 1.6 Kp, the capping percentage increased from 20 to 50%. It can be seen from Tables I and I1 that recompression and relaxation of probucol tablets give hard tablets which do not cap (Fig. 3). The friability decreases to an acceptable level (less that 1%). The thickness decreases with applied force, as expected (Fig. 4). The diameter is mostly unaffected by the recompression (Table 11). The data and experiments show that ( a ) the Hiestand principle (that capping can be prevented if relaxation can be made three dimensional) is applicable. It also shows that ( b ) a non-compressible outer coat in a double-compressionprocedure constitutes a means of imparting three-dimensional relaxation and allows compression of a product which otherwise could not be produced at acceptable hardness and/or without excessive capping. The validity of the principles stated above is not restricted to the particular outer polymer coat used here; any substance with an elastic limit higher than the second compression stress will work. For instance, pure magnesium stearate works as well.

Table Il-Physical Characteristics of Inner Tablets after Double Compression with a Non-Compressible Outer Layer

Group

Compression Force, Ib

Hardness,

Friability,

kg a

YO

~

A

A A

a

Diameter, cma

~

2000 6000 10,000

5.5 k 0.7 11.6 t 1.6 16.1 f 1.4

1.2 0.8 0.6

0.432 ? 0.010 0.414 2 0.005 0.4042 0.009

1.152 +. 0.005 1.1462 0.006 1.142& 0.005

2000 6000 10,000

6.6 f 0.5 13.0 2 0.8 16.7 ? 0.9

1.8 1 .o 0.7

0.450? 0.012 0.414f 0.006 0.404t 0.006

1.142? 0.008 1.1522 0.005 1.146 t 0.006

2000 6000 10,000

7.2 2 0.5 11.8 f 0.6 15.4 ? 1.1

1.4

0.452 f 0.008 0.422 ? 0.005 0.4052 0.009

1.136 ? 0.006 1.144 ? 0.006 1.150 f 0.012

Results are the mean

Table Ill-Effect

Thickness, cm a

_t

1 .O

0.8

SD of five determinations.

of Precompresslon Pressure on Hardness and Capping

Number of Tablets

Precornpression Pressure, Kp

Compression Pressure, Kp

10 5 10 10 10

0.6 0.6 0.6 0.6 0.6

0.7 3.1 6.8

10 10

1.2 1.2

1.6

10 10

2.8 2.8

3.7

1240 /Journal of Pharmaceutical Sciences Vol. 74, No. 77, November 1985

8.3

-

Hardness, KP

Number of Cappers

1 1 5.5 6.0 4.0

Very soft Very son

3.5 3.5

211 0 511 0

5.7 5.6

10110 1 Oil 0

10110 10110 10110

20

30

m

15

0

1

I

A

2

6

10

0

I

I

I

2

6

10

COMPRESSION PRESSURE COMPRESSION PRESSURE

(X

p s ~ )

Figure 3- Hardness versus second compression force of doublecompressed tablets. A, 8 and C refer to the groups in Tabte /.

References and Notes 1. Hiestand, E. N.; Peot, C. B.; Ochs, J. E. J . Pharrn. Sci. 1977,66, 510. 2. Amidon, G . E.; Smith, D. P.; Hiestand, E. N. J . Pharm. Sci. 1981, 70, 613. 3. Rue, P. J.; Barkworth, P. M. R.; Rid a Watt, P.; Rou ht P.; Sharland, D. C.; Seager, H.; Fisher, Ei;“ J . Pharm. &dnol. Prod. Manuf. 1979,1, 2-5.

Lt.

(X

Figure 4-Thickness as a function of second compression force. A, 8 and C refer to the groups in Table 1.

4. Carstensen, J. T. “Solid Pharmaceutics; Mechanical Properties and Rate Phenomena”; Academic Press: New York, 1981, p. 194.

Acknowledgments The authors thank Mr. Kenneth A. Adams for valuable technical assistance.

Journal of Pharmaceutical Sciences / 1241 Vol. 74, No. 7 1, November 7 985