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Correlation between the micromorphological parameters and residual solvent content of a crystalline steroid drug
Powder Technology 167 (2006) 104 – 107 www.elsevier.com/locate/powtec
Correlation between the micromorphological parameters and residual solvent content of a crystalline steroid drug Magdolna Hasznos-Nezdei a , József Kovács b , Sándor Kováts c , Amir Bashiri Shahroodi a , Piroska Szabó-Révész a,⁎ b
a University of Szeged, Institute of Pharmaceutical Technology, H-6720 Szeged, Eötvös u. 6, Hungary University of Veszprém, Department of Environmental Engineering and Chemical Technology, H-8201 Veszprém, Egyetem u. 10, Hungary c Gedeon Richter Ltd. H-1475 Budapest 10, P.O. Box 27, Hungary
Received 6 December 2005; received in revised form 19 April 2006; accepted 27 June 2006 Available online 8 August 2006
Abstract A small amount of solvents applied at the production of solid drugs is retained in the porous structure of the crystalline product. The regulatory guidelines require that the impurity due to the remaining solvent content of drugs should be a matter for serious concern toward marketing drugs; hence the reduction of the solvent amount is an important task of the technology of production. A steroid drug was crystallized and the correlation between the pore structure of the crystalline product and its residual solvent content was investigated. It was stated that the drug examined has a characteristic mesoand macropore structure, which distribution has a major contribution on the amount of the residual solvent content. © 2006 Elsevier B.V. All rights reserved. Keywords: Crystalline steroid; Micromorphology; Residual solvent; BET; BJH
1. Introduction Chemical purification is the last step in the course of production of drugs, as a result of which the pharmaceutical product have to have high purity and well defined physical and chemical parameters. Crystallization is the most frequent procedure of chemical purification in the case of solid drugs [1]. There are technological guidelines regulating both the production procedure and qualification of the crystalline product as well as requirements concerning both the kind of solvents used and the amount of the residual solvent content retained in the drug. The small quantity of solvent which is measured in the crystallized drug can be regarded as the accumulated residue of the various solvent(s) used in different steps of production pro⁎ Corresponding author. Department of Pharmaceutical Technology, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary. Tel.: +36 62 545572; fax: +36 62 545571. E-mail address: [email protected] (P. Szabó-Révész). 0032-5910/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2006.06.014
cedure. The residual solvent is a dose defined on the basis of the toxicological properties of the solvents used. This dose of solvent can be administered without the slightest risk of any toxic effect on the patient. The amount of the residue concerning different solvents is determined by validation and its value is limited for each drug [2,3]. The residual solvent content of the crystalline drug is located in the pores of the particulate product. The pores are formed by means of the agglomeration and arrangement of elemental crystals in the course of crystal precipitation. The mechanism of pore formation is considerably influenced by the properties of the drug and the solvent used, by their interaction during nucleation and crystal growth and also by the change of the technological parameters. The solvent is adhered to the lattice element of the porous surface by physical adsorption and may be located in the pores of appropriate size in a condensed state. On the course of drying, homogenization (possibly grinding) after crystallization the solvent content of the porous substance usually decreases, however, a small amount of solvent may be retained in the small
M. Hasznos-Nezdei et al. / Powder Technology 167 (2006) 104–107
pores. According to literature [4], pores of various sizes may be formed in solid substances: micropore b 2 nm; mesopore 2 50 nm and macropore N 50 nm:
105
residual solvent content was investigated. The microstructure of the crystalline drug was characterized by BET (specific surface area) and BJH (pore volume, pore diameter) methods and the quantity of solvent retained in the crystallized product was determined on gas chromatograph. 2. Material and methods
The size and distribution of the pores as well as the size of pore volume can be measured by N2 gas adsorption. The surface of the crystalline solid substance can also be calculated from these adsorption data. The total surface area is the sum of the value of the outer and inner surfaces. The outer surface originates from the geometrical size of the solid substance, while the inner surface results from the surface of the pores. The inner surface is frequently greater with two or three orders of magnitude than the outer one [5]. The specific surface area can be determined with the Langmuir equation or with the Brunauer, Emmett and Teller (BET) equation depending on the shape of the adsorption isotherm [6,7]. Langmuir's theory can be applied in the case of monomolecular adsorption, which is the typical case of microporous solid substances. In case of substances having meso- and macropores as well, the multilayer adsorption takes place; which can be evaluated with the BET equation. The pore volume can be calculated from the amount of gas adsorbed on the solid surface (adsorption and desorption isotherm). According to the Barrett, Joyner and Halenda (BJH) theory, the pore volume of pores of 1.7–300 nm size in diameter can be given [8]. Based on the BJH theory, the pore diameter (Dp) can be determined by the following equation: Dp ¼ Dk þ 2d t
ð1Þ
The value of Dk on the basis of the Kelvin equation is Dk ¼ −
4d V0 d r d cos/ R d T d ln pp0
ð2Þ
while layer thickness t can be calculated with the help of Halsey's relationship: !0:333 −5:00 t ¼ 0:354d ð3Þ ln pp0 where Dp—pore diameter, t—adsorbed layer thickness, Dk— pore inner (Kelvin) diameter filled with condensate, V0—gas molecular volume, σ—surface tension, ϕ—contact angle of liquid nitrogen in the pores, R—gas constant, T—absolute temperature, p/p0—relative pressure. Based on the gas adsorption data, the BJH pore volume distribution can be given for the solid substance, which makes a correlation between pore volume (Vp) and pore diameter (Dp) distribution: Vp ⇔Dp
DVp ⇔Dp DDp
DVp ⇔Dp DlogDp
ð4Þ
In this work a steroid drug was crystallized and the correlation between the pore structure of the crystalline product and its
2.1. Material Norgestrel as a steroid drug was used as the model substance, which was crystallized from the 1:1 mixture of isopropanol– acetonitrile in the final step of the production technology. Under industrial circumstances the crystallization was carried out by cooling and subsequent evaporation crystallization. 2.2. Experimental methods 2.2.1. Gas adsorption investigations The specific surface areas, the micropore volume and the pore diameter of the samples were determined with ASAP 2000 equipment (Micromeritics Instrument Corp., Norcross, GA, USA) from the data of nitrogen adsorption and desorption isotherms at the boiling point of liquid nitrogen under atmospheric pressure (77.3 K). The specific surface area was calculated in the validity range of the BET isotherm from the slope and intercept of a line characterized by five measuring points. The samples (1.5– 2.0 g) were degassed at 25 °C in a vacuum up to 10 Pa absolute pressure. After degassing, the samples were weighed again and the morphological parameters were calculated for the “surfacecleaned” masses of the samples. The micropore volume and the pore diameter were calculated via the BJH method. The investigations were repeated three times. 2.2.2. Other examinations The small quantity of solvent retained in the crystalline product was determined on gas chromatograph, with an HP 5890 type (Hewlett Packard, Avondale, PA, USA) equipment using SPB-1 60 m × 0.25 mm column with 1 μm film thickness. The requirements for maximum residual solvent content are the following: 3000 ppm for acetonitrile (AN) and 2000 ppm for isopropanol (IPA). The particle size of the samples was determined with a 2600c type laser diffraction analyzer (Malvern Instruments Ltd., Spring Lane South, England). 3. Results and discussion The particle size, the microstructure of the crystalline product and also the value of the residual solvent content showed considerable differences according to the different technological parameters. The morphological data of the crystallized samples are summarized in Table 1. The particle size data show the sizes of the cumulative distribution curve (corresponding to 10%, 50% and 90%). Dp denotes the average pore diameter. The characteristic parameters of the selected samples cover a wide range. This wide range makes available the evaluation of the correlation between the size distribution data and the micromorphological properties.
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Table 1 Morphological parameters of crystalline material
Table 2 Correlation between the pore parameters and residual solvent content
Sample Particle size (μm) label D(v, 0.1) D(v, 0.5) D(v,
Sample label
K/01 K/03 K/04 9F 29N 90N 91N
2.3 1.6 2.5 2.7 4.1 3.9 5.1
5.1 3.9 6.0 6.4 16.3 16.6 20.7
14.6 9.3 17.8 19.2 48.8 53.0 61.9
Micromorphological parameters 0.9)
FBET (m2/g) Vp (*104 cm3/g) Dp (nm) 1.76 3.47 2.84 2.70 0.90 1.08 0.87
311.3 108.9 61.3 75.5 17.2 25.3 19.1
62.3 11.9 7.94 9.5 8.0 8.0 7.1
The data of particle size distribution provide information about the structure of the crystalline substance in the micrometer range, while the micromorphological properties quantify the agglomeration and arrangement of elemental crystals of nanometre size. Accordingly, it is not easy to evaluate the correlation between the two groups of data. The specific surface area (FBET) can be an evaluating parameter. The value of the surface fraction determined by the particle size and the pore characteristics varies considerably from sample to sample. Sample K/01 has the smallest specific surface as it has the smallest inner surface. Due to the large pore size, the value of pore volume is high, but this gives a much smaller inner surface than in the case of the other two samples. The outer surface is the largest in the case of sample K/03 as a result of the small particle size, and the inner surface given by the pores is also greater than for sample K/04. The comparison of the pore volume distribution curves of the previous three samples (Fig. 1) makes available the more correct evaluation of the data than that of Table 1. This is a graphic way of illustrating the similarities and differences in the microstructures of the samples presented in Table 1. The pore size encompasses a wide range (between 1.7 and 150 nm) for all three samples, that is they contain mesopores (2–50 nm) and macropores (N50 nm), the proportion of which differs largely in case of the samples examined. The pore structure of sample K/01 differs from the other two samples considerably as the pore volume is almost entirely given by the volume of pores N20 nm, the volume fraction of
K/01 K/03 K/04 9F 29N 90N 91N
Pore parameters
Residual solvent (ppm)
Vp (*104 cm3/g)
Dp (nm)
IPA
AN
311.3 108.9 61.3 75.5 17.2 25.3 19.1
62.3 11.9 7.9 9.5 8.0 8.0 7.1
1830 2890 1590 1460 490 710 450
2260 3700 2620 2300 910 1560 930
pores b 20 nm is negligible. In samples K/03 and K/04 the volume fraction of pores b 20 nm can be regarded as almost the same, but there is difference between the two samples in the range of N20 nm. Sample K/04 was found to have the smallest value of cumulative pore volume. The correlation between the micromorphological parameters and the residual solvent content is introduced in Table 2 in which (in addition to the samples presented in Table 1) pore properties and residual solvent content values are given for four additional samples as well. It can be expected that the pore size and pore volume may play an important role with respect to residual solvent content. To prove the previous expectation, data of Table 2 were evaluated. The given samples constitute two series of experiments. Samples K/01, K/03 and K/04 belong to the first series, in which the value of the residual solvent is relatively high. In sample K/03 the value of the residual solvent is much greater than the permitted one and this cannot be interpreted on the basis of pore volume Vp. The residual solvent contents of samples K/01 and K/04 do not show a significant difference in spite of the approximately fivefold ratio of the value of the pore volume. This indicates that it is not pore volume Vp which has a decisive role with respect to residual solvent content, but probably the volume of a certain sized pore volume range is decisive, from which the solvent cannot disappear during the drying of the product which is probably due to the retaining effect of the capillary forces. This expectation is
Fig. 1. Cumulative pore volume distribution of crystallized steroid samples.
M. Hasznos-Nezdei et al. / Powder Technology 167 (2006) 104–107
107
Fig. 2. Cumulative pore volume distributions.
supported by the cumulative volume distribution curves (Fig. 1), which clearly illustrate the differences between the microstructures of these samples. A relatively small range of the K/01 distribution curve retains a similar amount of solvent as sample K/04. The numerical evaluation of the cumulative volume distribution curves of Fig. 1 reveals that this pore size range is b50 nm for sample K/01, and a volume fraction of 45–50 * 10− 4 cm3/g can be associated with it. In the case of sample K/03 a cumulative pore volume value of 60 * 10− 4 cm3/g was obtained for this range, and a value of ∼ 40 * 10− 4 cm3/g for sample K/04 (slightly smaller than for K/01). For sample K/01 the pore volume fraction of the size range larger than mesopores (50 nm) was considerably larger compared to samples K/03 and K/04, but this size range was not found to play a role with respect to the amount of the residual solvent content. Fig. 2 shows the cumulative pore volume distribution curves of the additional four samples. The values of the residual solvent contents are incorporated next to the cumulative distribution curves. In sample 9F the value of the residual solvent is similar in size to that of samples K/01 and K/04 discussed above (1460, 2300). According to the numerical evaluation of the 9F cumulative volume distribution curve, the volume of the b 50 nm pores is 48 * 10− 4 cm3/g, which is similar in size to the values obtained with samples K/01 and K/04. The cumulative pore volume is considerably smaller for the other three samples, and accordingly the value of the residual solvent is also much lower. Samples 91N and 29N have almost the same microstructure with very little residual solvent content. The residual solvent of 90N is almost twice as much as that of the previous samples. The differences in pore volume (belonging to the size range of b50 nm) determining the quantity of the residual solvent content can be seen clearly in the shape of the cumulative pore volume distribution curves. 4. Conclusions The analysis of the correlation between the quantity of the residual solvent content and cumulative pore volume distribution of crystalline steroid material shows that those samples can
be expected to have a low amount of residual solvent content which have a pore volume value smaller than 50 * 10− 4 cm3/g. The numerical evaluation of the pore volume distribution curves reveal that the quantity of the residual solvent content measured in the crystalline drug is retained in mesopores (b 50 nm). Acknowledgement The authors gratefully acknowledge the support provided for this study by the Hungarian National Research Foundation (OTKA T-026224 and T-047166). References [1] P. Szabó-Révész, H. Göczö, K. Pintye-Hódi, P. Kása Jr., I. Erös, M. Hasznos-Nezdei, B. Farkas, Development of spherical crystal agglomerates of an aspartic acid salt for direct tablet making, Powder Technol. 114 (2001) 118–124. [2] A.M. Dwidevi, Residual solvent analysis in pharmaceuticals, Pharm. Technol. Eur. 14 (2002) 26–28. [3] M. Bauer, L. de Leede, M. Van Der Waart, Purity as an issue in pharmaceutical research and development, Eur. J. Pharm. Sci. 6 (1998) 331–335. [4] IUPAC Manual of Symbols and Terminology of Colloid Surfaces, Butterworths, London, 1982. [5] M.A. Ramos, M.H. Gil, E. Schacht, G. Matthys, W. Mondelaers, M.M. Figueiredo, Physical and chemical characterisation of some silicas and silica derivatives, Powder Technol. 99 (1998) 79–85. [6] V. Gómez-Serrano, C.M. González-Garcia, M.J. González-Martin, Nitrogen adsorption isotherms on carbonaceous materials. Comparison of BET and Langmuir surface areas, Powder Technol. 116 (2001) 103–108. [7] S. Brunnauer, P.H. Emmett, E. Teller, Adsorption of gases in multimolecular layers, J. Am. Chem. Soc. 60 (1938) 309–316. [8] E.P. Barrett, L.G. Joyner, P.P. Halenda, The determination of pore volume and area distributions in porous substances. Computations from nitrogen isotherms, J. Am. Chem. Soc. 73 (1951) 373–380.
Correlation between the micromorphological parameters and residual solvent content of a crystalline steroid drug Magdolna Hasznos-Nezdei a , József Kovács b , Sándor Kováts c , Amir Bashiri Shahroodi a , Piroska Szabó-Révész a,⁎ b
a University of Szeged, Institute of Pharmaceutical Technology, H-6720 Szeged, Eötvös u. 6, Hungary University of Veszprém, Department of Environmental Engineering and Chemical Technology, H-8201 Veszprém, Egyetem u. 10, Hungary c Gedeon Richter Ltd. H-1475 Budapest 10, P.O. Box 27, Hungary
Received 6 December 2005; received in revised form 19 April 2006; accepted 27 June 2006 Available online 8 August 2006
Abstract A small amount of solvents applied at the production of solid drugs is retained in the porous structure of the crystalline product. The regulatory guidelines require that the impurity due to the remaining solvent content of drugs should be a matter for serious concern toward marketing drugs; hence the reduction of the solvent amount is an important task of the technology of production. A steroid drug was crystallized and the correlation between the pore structure of the crystalline product and its residual solvent content was investigated. It was stated that the drug examined has a characteristic mesoand macropore structure, which distribution has a major contribution on the amount of the residual solvent content. © 2006 Elsevier B.V. All rights reserved. Keywords: Crystalline steroid; Micromorphology; Residual solvent; BET; BJH
1. Introduction Chemical purification is the last step in the course of production of drugs, as a result of which the pharmaceutical product have to have high purity and well defined physical and chemical parameters. Crystallization is the most frequent procedure of chemical purification in the case of solid drugs [1]. There are technological guidelines regulating both the production procedure and qualification of the crystalline product as well as requirements concerning both the kind of solvents used and the amount of the residual solvent content retained in the drug. The small quantity of solvent which is measured in the crystallized drug can be regarded as the accumulated residue of the various solvent(s) used in different steps of production pro⁎ Corresponding author. Department of Pharmaceutical Technology, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary. Tel.: +36 62 545572; fax: +36 62 545571. E-mail address: [email protected] (P. Szabó-Révész). 0032-5910/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2006.06.014
cedure. The residual solvent is a dose defined on the basis of the toxicological properties of the solvents used. This dose of solvent can be administered without the slightest risk of any toxic effect on the patient. The amount of the residue concerning different solvents is determined by validation and its value is limited for each drug [2,3]. The residual solvent content of the crystalline drug is located in the pores of the particulate product. The pores are formed by means of the agglomeration and arrangement of elemental crystals in the course of crystal precipitation. The mechanism of pore formation is considerably influenced by the properties of the drug and the solvent used, by their interaction during nucleation and crystal growth and also by the change of the technological parameters. The solvent is adhered to the lattice element of the porous surface by physical adsorption and may be located in the pores of appropriate size in a condensed state. On the course of drying, homogenization (possibly grinding) after crystallization the solvent content of the porous substance usually decreases, however, a small amount of solvent may be retained in the small
M. Hasznos-Nezdei et al. / Powder Technology 167 (2006) 104–107
pores. According to literature [4], pores of various sizes may be formed in solid substances: micropore b 2 nm; mesopore 2 50 nm and macropore N 50 nm:
105
residual solvent content was investigated. The microstructure of the crystalline drug was characterized by BET (specific surface area) and BJH (pore volume, pore diameter) methods and the quantity of solvent retained in the crystallized product was determined on gas chromatograph. 2. Material and methods
The size and distribution of the pores as well as the size of pore volume can be measured by N2 gas adsorption. The surface of the crystalline solid substance can also be calculated from these adsorption data. The total surface area is the sum of the value of the outer and inner surfaces. The outer surface originates from the geometrical size of the solid substance, while the inner surface results from the surface of the pores. The inner surface is frequently greater with two or three orders of magnitude than the outer one [5]. The specific surface area can be determined with the Langmuir equation or with the Brunauer, Emmett and Teller (BET) equation depending on the shape of the adsorption isotherm [6,7]. Langmuir's theory can be applied in the case of monomolecular adsorption, which is the typical case of microporous solid substances. In case of substances having meso- and macropores as well, the multilayer adsorption takes place; which can be evaluated with the BET equation. The pore volume can be calculated from the amount of gas adsorbed on the solid surface (adsorption and desorption isotherm). According to the Barrett, Joyner and Halenda (BJH) theory, the pore volume of pores of 1.7–300 nm size in diameter can be given [8]. Based on the BJH theory, the pore diameter (Dp) can be determined by the following equation: Dp ¼ Dk þ 2d t
ð1Þ
The value of Dk on the basis of the Kelvin equation is Dk ¼ −
4d V0 d r d cos/ R d T d ln pp0
ð2Þ
while layer thickness t can be calculated with the help of Halsey's relationship: !0:333 −5:00 t ¼ 0:354d ð3Þ ln pp0 where Dp—pore diameter, t—adsorbed layer thickness, Dk— pore inner (Kelvin) diameter filled with condensate, V0—gas molecular volume, σ—surface tension, ϕ—contact angle of liquid nitrogen in the pores, R—gas constant, T—absolute temperature, p/p0—relative pressure. Based on the gas adsorption data, the BJH pore volume distribution can be given for the solid substance, which makes a correlation between pore volume (Vp) and pore diameter (Dp) distribution: Vp ⇔Dp
DVp ⇔Dp DDp
DVp ⇔Dp DlogDp
ð4Þ
In this work a steroid drug was crystallized and the correlation between the pore structure of the crystalline product and its
2.1. Material Norgestrel as a steroid drug was used as the model substance, which was crystallized from the 1:1 mixture of isopropanol– acetonitrile in the final step of the production technology. Under industrial circumstances the crystallization was carried out by cooling and subsequent evaporation crystallization. 2.2. Experimental methods 2.2.1. Gas adsorption investigations The specific surface areas, the micropore volume and the pore diameter of the samples were determined with ASAP 2000 equipment (Micromeritics Instrument Corp., Norcross, GA, USA) from the data of nitrogen adsorption and desorption isotherms at the boiling point of liquid nitrogen under atmospheric pressure (77.3 K). The specific surface area was calculated in the validity range of the BET isotherm from the slope and intercept of a line characterized by five measuring points. The samples (1.5– 2.0 g) were degassed at 25 °C in a vacuum up to 10 Pa absolute pressure. After degassing, the samples were weighed again and the morphological parameters were calculated for the “surfacecleaned” masses of the samples. The micropore volume and the pore diameter were calculated via the BJH method. The investigations were repeated three times. 2.2.2. Other examinations The small quantity of solvent retained in the crystalline product was determined on gas chromatograph, with an HP 5890 type (Hewlett Packard, Avondale, PA, USA) equipment using SPB-1 60 m × 0.25 mm column with 1 μm film thickness. The requirements for maximum residual solvent content are the following: 3000 ppm for acetonitrile (AN) and 2000 ppm for isopropanol (IPA). The particle size of the samples was determined with a 2600c type laser diffraction analyzer (Malvern Instruments Ltd., Spring Lane South, England). 3. Results and discussion The particle size, the microstructure of the crystalline product and also the value of the residual solvent content showed considerable differences according to the different technological parameters. The morphological data of the crystallized samples are summarized in Table 1. The particle size data show the sizes of the cumulative distribution curve (corresponding to 10%, 50% and 90%). Dp denotes the average pore diameter. The characteristic parameters of the selected samples cover a wide range. This wide range makes available the evaluation of the correlation between the size distribution data and the micromorphological properties.
106
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Table 1 Morphological parameters of crystalline material
Table 2 Correlation between the pore parameters and residual solvent content
Sample Particle size (μm) label D(v, 0.1) D(v, 0.5) D(v,
Sample label
K/01 K/03 K/04 9F 29N 90N 91N
2.3 1.6 2.5 2.7 4.1 3.9 5.1
5.1 3.9 6.0 6.4 16.3 16.6 20.7
14.6 9.3 17.8 19.2 48.8 53.0 61.9
Micromorphological parameters 0.9)
FBET (m2/g) Vp (*104 cm3/g) Dp (nm) 1.76 3.47 2.84 2.70 0.90 1.08 0.87
311.3 108.9 61.3 75.5 17.2 25.3 19.1
62.3 11.9 7.94 9.5 8.0 8.0 7.1
The data of particle size distribution provide information about the structure of the crystalline substance in the micrometer range, while the micromorphological properties quantify the agglomeration and arrangement of elemental crystals of nanometre size. Accordingly, it is not easy to evaluate the correlation between the two groups of data. The specific surface area (FBET) can be an evaluating parameter. The value of the surface fraction determined by the particle size and the pore characteristics varies considerably from sample to sample. Sample K/01 has the smallest specific surface as it has the smallest inner surface. Due to the large pore size, the value of pore volume is high, but this gives a much smaller inner surface than in the case of the other two samples. The outer surface is the largest in the case of sample K/03 as a result of the small particle size, and the inner surface given by the pores is also greater than for sample K/04. The comparison of the pore volume distribution curves of the previous three samples (Fig. 1) makes available the more correct evaluation of the data than that of Table 1. This is a graphic way of illustrating the similarities and differences in the microstructures of the samples presented in Table 1. The pore size encompasses a wide range (between 1.7 and 150 nm) for all three samples, that is they contain mesopores (2–50 nm) and macropores (N50 nm), the proportion of which differs largely in case of the samples examined. The pore structure of sample K/01 differs from the other two samples considerably as the pore volume is almost entirely given by the volume of pores N20 nm, the volume fraction of
K/01 K/03 K/04 9F 29N 90N 91N
Pore parameters
Residual solvent (ppm)
Vp (*104 cm3/g)
Dp (nm)
IPA
AN
311.3 108.9 61.3 75.5 17.2 25.3 19.1
62.3 11.9 7.9 9.5 8.0 8.0 7.1
1830 2890 1590 1460 490 710 450
2260 3700 2620 2300 910 1560 930
pores b 20 nm is negligible. In samples K/03 and K/04 the volume fraction of pores b 20 nm can be regarded as almost the same, but there is difference between the two samples in the range of N20 nm. Sample K/04 was found to have the smallest value of cumulative pore volume. The correlation between the micromorphological parameters and the residual solvent content is introduced in Table 2 in which (in addition to the samples presented in Table 1) pore properties and residual solvent content values are given for four additional samples as well. It can be expected that the pore size and pore volume may play an important role with respect to residual solvent content. To prove the previous expectation, data of Table 2 were evaluated. The given samples constitute two series of experiments. Samples K/01, K/03 and K/04 belong to the first series, in which the value of the residual solvent is relatively high. In sample K/03 the value of the residual solvent is much greater than the permitted one and this cannot be interpreted on the basis of pore volume Vp. The residual solvent contents of samples K/01 and K/04 do not show a significant difference in spite of the approximately fivefold ratio of the value of the pore volume. This indicates that it is not pore volume Vp which has a decisive role with respect to residual solvent content, but probably the volume of a certain sized pore volume range is decisive, from which the solvent cannot disappear during the drying of the product which is probably due to the retaining effect of the capillary forces. This expectation is
Fig. 1. Cumulative pore volume distribution of crystallized steroid samples.
M. Hasznos-Nezdei et al. / Powder Technology 167 (2006) 104–107
107
Fig. 2. Cumulative pore volume distributions.
supported by the cumulative volume distribution curves (Fig. 1), which clearly illustrate the differences between the microstructures of these samples. A relatively small range of the K/01 distribution curve retains a similar amount of solvent as sample K/04. The numerical evaluation of the cumulative volume distribution curves of Fig. 1 reveals that this pore size range is b50 nm for sample K/01, and a volume fraction of 45–50 * 10− 4 cm3/g can be associated with it. In the case of sample K/03 a cumulative pore volume value of 60 * 10− 4 cm3/g was obtained for this range, and a value of ∼ 40 * 10− 4 cm3/g for sample K/04 (slightly smaller than for K/01). For sample K/01 the pore volume fraction of the size range larger than mesopores (50 nm) was considerably larger compared to samples K/03 and K/04, but this size range was not found to play a role with respect to the amount of the residual solvent content. Fig. 2 shows the cumulative pore volume distribution curves of the additional four samples. The values of the residual solvent contents are incorporated next to the cumulative distribution curves. In sample 9F the value of the residual solvent is similar in size to that of samples K/01 and K/04 discussed above (1460, 2300). According to the numerical evaluation of the 9F cumulative volume distribution curve, the volume of the b 50 nm pores is 48 * 10− 4 cm3/g, which is similar in size to the values obtained with samples K/01 and K/04. The cumulative pore volume is considerably smaller for the other three samples, and accordingly the value of the residual solvent is also much lower. Samples 91N and 29N have almost the same microstructure with very little residual solvent content. The residual solvent of 90N is almost twice as much as that of the previous samples. The differences in pore volume (belonging to the size range of b50 nm) determining the quantity of the residual solvent content can be seen clearly in the shape of the cumulative pore volume distribution curves. 4. Conclusions The analysis of the correlation between the quantity of the residual solvent content and cumulative pore volume distribution of crystalline steroid material shows that those samples can
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