International Journal of Pharmaceutics 269 (2004) 433–442
`
`Moisture sorption by cellulose powders
`of varying crystallinity
`Albert Mihranyan a, Assumpcio Piñas Llagostera b,
`Richard Karmhag c, Maria Strømme c, Ragnar Ek a,∗
`
`a Department of Pharmacy, BMC, Uppsala University, Box 580, 75123 Uppsala, Sweden
`b Department of Pharmacy, Barcelona University, Joan XXIII s/n, 08028 Barcelona, Spain
`c Department of Engineering Sciences, The Ångström Laboratory, Uppsala University, Box 534, 75121 Uppsala, Sweden
`
`Received 27 March 2003; received in revised form 18 September 2003; accepted 24 September 2003
`
`Abstract
`
`Moisture in microcrystalline cellulose may cause stability problems for moisture sensitive drugs. The aim of this study was
`to investigate the influence of crystallinity and surface area on the uptake of moisture in cellulose powders. Powders of varying
`crystallinity were manufactured, and the uptake of moisture was investigated at different relative humidities. The structure of the
`cellulose powders was characterized by X-ray diffraction, BET surface area analysis, and scanning electron microscopy. Moisture
`uptake was directly related to the cellulose crystallinity and pore volume: Cellulose powders with higher crystallinity showed
`lower moisture uptake at relative humidities below 75%, while at higher humidities the moisture uptake could be associated with
`filling of the large pore volume of the cellulose powder of highest crystallinity. In conclusion, the structure of cellulose should
`be thoroughly considered when manufacturing low moisture grades of MCC.
`© 2003 Elsevier B.V. All rights reserved.
`
`Keywords: Microcrystalline cellulose; Algae cellulose; Moisture sorption; Cellulose structure
`
`1. Introduction
`
`Microcrystalline cellulose (MCC) is one of the most
`commonly used tabletting excipients (Bolhuis and
`Chowhan, 1995) and many of its properties depend on
`its moisture content (Ahlneck and Alderborn, 1988;
`Ahlneck and Zografi, 1990; Amidon and Houghton,
`1995). However, moisture sorption by MCC has also
`been reported to cause stability problems for moisture
`sensitive drugs (Carstensen et al., 1969; Genton and
`Kesselelring, 1977; Carstensen and Lothari, 1983).
`
`Corresponding author. Tel.: +46-18-471-41-12;
`∗
`fax: +46-18-471-42-23.
`E-mail address: Ragnar.Ek@farmaci.uu.se (R. Ek).
`
`Ordinary MCC is manufactured with 4–5% (w/w)
`moisture content (European Pharmacopoeia, 2002).
`For moisture sensitive drugs, low moisture grades of
`MCC are available (1.5%, w/w, moisture in Avicel PH
`112 and 3%, w/w, moisture in Avicel PH 103, FMC
`Corp.); however, these appear hygroscopic (Doelker
`et al., 1995).
`In general, vapor sorption can occur either on
`the surfaces or in the bulk of a material. Moisture
`uptake by cellulose powder is recognized as predom-
`inantly occurring in the bulk of disordered regions
`(Howsman, 1949). Absorption of moisture in the bulk
`of disordered regions of cellulose particles has been
`widely accepted as the reason for manifold differences
`between BET N2 and BET H2O surface area values
`
`0378-5173/$ – see front matter © 2003 Elsevier B.V. All rights reserved.
`doi:10.1016/j.ijpharm.2003.09.030
`
`MYLAN - EXHIBIT 1007
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`
`(Zografi et al., 1984; Zografi and Kontny, 1986). One
`complication in understanding the mechanisms of
`moisture sorption and its dependence on the material’s
`structure is the complexity of the cellulose structure.
`Therefore, the applicability of the term amorphous
`(or “liquid-like”) in its original meaning is some-
`times questionable. Whilst X-ray diffraction analysis
`clearly indicates various degrees of order in cellulose,
`many parameters (e.g. Tg, “glassy-rubbery” state
`transitions, etc.) directly associated with the amor-
`phous state cannot be reliably reproduced (Stubberud
`et al., 1996). Verlhac et al. (1990) suggested that
`what appears to be “amorphous” cellulose consists
`mainly of surface chains. A clear relationship between
`availability of surface hydroxyl groups and cellulose
`crystallinity was established.
`Varying the crystallinity of cellulose powder is
`expected to cause changes in the moisture content.
`In order to investigate the influence of the struc-
`tural properties of cellulose on moisture sorption,
`it is necessary to select cellulose powders over a
`broad range of crystallinities. The crystallinity may
`be altered by various methods: The disordered state
`in cellulose can be induced either by addition of
`swelling agents (Patil et al., 1965) or by grinding
`(Suzuki and Nakagami, 1999), whereas extraction of
`cellulose from cell walls of certain algae is reported
`to produce highly crystalline cellulose (Ek et al.,
`1998).
`The aim of this study is to, for the first time, show
`how structural properties, such as surface area, pore
`volume, and crystallinity, are interconnected when in-
`fluencing the cellulose powder’s ability to interact with
`moisture. The study is performed over a broad range
`of cellulose crystallinities and surface areas includ-
`ing, a.o., cellulose powders of algal origin. As a con-
`sequence of this, unique SEM pictures together with
`physical characteristics of the algal celluloses will also
`be presented.
`
`2. Materials and methods
`
`2.1. Materials
`
`Five different types of cellulose were used: mi-
`crocrystalline cellulose (MCC, Avicel PH 102, FMC,
`Ireland), agglomerated micronized cellulose (AMC),
`
`low crystallinity cellulose (LCC), Algiflor brown al-
`gae cellulose (Algiflor, Danisco, France), and Clado-
`phora green algae cellulose (Cladophora glomerata
`harvested from the Baltic Sea). The Algiflor brown al-
`gae were a blend of five species: Laminaria digitata,
`Lessonia nigrescens, Macrocystis pyrifera, Ascophyl-
`lum nodosum, and Fucus serratus.
`
`2.1.1. Agglomerated micronized cellulose (AMC)
`To produce AMC, MCC was ground in a mortar
`mill (Retsch KM 1, Germany) for 2 h with water (1 ml
`of water per 2 g of powder). A 10% suspension of
`the resultant powder (w/v) was then spray-dried (Mi-
`nor Type 53, Niro Atomizer A.S., Denmark) at Tin =
`C and Tout = 95–100
`◦
`◦
`C with a feed-rate of
`205–210
`1.7 l/h.
`
`2.1.2. Low crystallinity cellulose (LCC)
`To produce LCC, 50 g of MCC was dispersed in
`1 l of 70% ZnCl2 solution and vigorously stirred.
`After allowing it to swell for 1 h, the cellulose was
`precipitated with additional water. The resultant pow-
`der was washed repeatedly until the conductivity of
`the washed water approximated that of deionised
`−6 S/cm) and, thereafter, spray-dried as
`water (i.e. 10
`described above.
`
`2.1.3. Cladophora and Algiflor algae cellulose
`Five hundred grams of algae (i.e. Cladophora green
`algae and Algiflor brown algae) were bleached with
`180 g of NaClO2 in 0.5 l acetic buffer. The mixture
`was diluted to 5 l, poured into a plastic bag and
`◦
`stored in a water-bath for 3 h at 60
`C. The product
`was washed until neutrality (pH ∼7) as indicated by
`coloration of a paper indicator (Universalindikator,
`Merck, Sweden) and filtered. Three liters of 0.5 M
`NaOH was added to the remainder, and the resul-
`◦
`tant product was stored at 60
`C in a water-bath
`overnight. The resultant pulp was washed till neu-
`trality, filtered, and dried at room temperature. Dry,
`purified algae were ground prior to acidic hydrolysis
`(Fitz Mill type D6, Manesty Machines, UK). To 50 g
`of the product 1 l of 5% HCl was added, and the
`suspension was heated till boiling. Once boiling, it
`was removed from the heat, and the slurry was al-
`lowed to stand overnight. The remainder was washed
`till neutrality, filtered and spray-dried as described
`above.
`
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`
`435
`
`2.2. Methods
`
`3. Results
`
`2.2.1. Scanning electron microscopy
`Micrographs of each sample were taken (Leo Gem-
`ini 1550 FEG SEM, UK) at a 100,000 magnifica-
`tion. The samples of each powder were mounted onto
`double-sided sticky tape over aluminium stubs and
`coated with gold under vacuum prior to the studies.
`
`2.2.2. X-ray diffraction
`An X-ray diffractometer with Bragg-Brentano ge-
`ometry was used (Diffraktometer D5000, Siemens,
`Germany). The Cu K␣ radiation was utilized (λ =
`◦
`1.54 Å) and the angle 2θ was set between 10 and 45
`.
`The crystallinity index was calculated as
`
`CrI = I002 − Iam
`
`I002
`
`(1)
`
`where I002 is the overall intensity of the peak at 2θ
`◦
`about 22
`and Iam is the intensity of the baseline at 2θ
`◦
`(Segal et al., 1959).
`about 18
`
`2.2.3. Moisture sorption
`The moisture content was measured gravimetri-
`◦
`C over
`cally after samples had been stored at 25
`saturated salt solutions of LiCl, CH3COOK, K2CO3,
`NaBr, NaCl, and KNO3 corresponding to 11, 25, 40,
`63, 75, and 96% relative humidity (RH), respectively
`(Nyqvist, 1983) for at least 48 h. Prior to the mea-
`surements, the samples were stored over P2O5 (0%
`RH) for 10 days.
`
`2.2.4. Surface area and porosity
`The specific surface area of the powders was ob-
`tained from a BET (Brunauer et al., 1938) analysis
`of N2 adsorption isotherms (ASAP 2010, Micromet-
`rics, USA). The total pore volume of the powders
`was obtained as the volume of adsorbed nitrogen at
`relative pressure approximating unity. The weight of
`the samples in these measurements was chosen so as
`to produce a total surface of 5–10 m2. The surface
`area available for water adsorption was calculated
`based on the principles described by Brunauer et al.
`(1938) and the assumption that each water molecule
`occupies a surface area of 12.3 Å2 (Wefers, 1964).
`The method is applicable for relative humidities
`below 40%.
`
`3.1. Scanning electron microscopy
`
`Fig. 1 illustrates the texture of the cellulose samples
`as obtained by SEM. The surface of the LCC particles
`was smooth: a similar texture was visible in the MCC
`particles. The surface of the AMC particles was irreg-
`ular, whereas the Algiflor cellulose particles appeared
`deeply grooved. In the Cladophora cellulose sample,
`a web-like structure composed of numerous filaments
`was visible.
`
`3.2. X-ray diffraction
`
`The X-ray diffraction patterns of the samples are
`presented in Fig. 2. As a result of the chemical treat-
`ment, a smeared out diffractogram was observed in
`LCC indicating a high degree of disorder. From the
`AMC panel, we observe that grinding MCC was less
`efficient in reducing crystallinity than was the chem-
`ical treatment. The MCC diffractogram revealed a
`◦
`relatively ordered structure with a narrow peak at 22
`◦
`and a diffuse peak between 13 and 18
`. Two peaks
`◦
`of low intensity at 14 and 16
`were identified in the
`Algiflor cellulose sample; however, these were dif-
`fused in pattern, indicating lower degree of order than
`seen in Cladophora cellulose powder. Sharp, distinct
`◦
`peaks at around 14, 16, and 22
`as well as a small
`◦
`peak at 20
`featured the Cladophora cellulose sample,
`characterizing this material as highly crystalline. The
`corresponding crystallinity indices are summarized in
`Table 1.
`
`3.3. Moisture sorption
`
`The moisture sorption isotherms are presented in
`Fig. 3. Below 75% RH, the moisture sorption was
`higher for materials with a lower crystallinity index.
`At very high relative humidities, the moisture con-
`tent of the Cladophora cellulose powder increased
`sharply. The level of hysteresis between the sorption
`and desorption curves was broader for materials with
`a lower crystallinity index. In Fig. 4, the moisture
`content of the samples is plotted as a function of their
`crystallinity index at different relative humidities. The
`moisture content of the materials decreased steadily
`at RHs between 11 and 75%. At higher RHs, the
`
`

`

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`A. Mihranyan et al. / International Journal of Pharmaceutics 269 (2004) 433–442
`
`Fig. 1. SEM micrographs of cellulose powders at 100,000× magnification.
`
`

`

`A. Mihranyan et al. / International Journal of Pharmaceutics 269 (2004) 433–442
`
`437
`
`LCC
`
`Algiflor
`
`AMC
`
`Cladophora
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`2 theta degrees
`
`MCC
`
`250
`
`200
`
`150
`
`100
`
`50
`
`0
`
`Cps
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`2 theta degrees
`
`Fig. 2. X-ray diffraction patterns of cellulose powders of varying crystallinity.
`
`250
`
`200
`
`150
`
`100
`
`50
`
`0
`
`250
`
`200
`
`150
`
`100
`
`50
`
`0
`
`Cps
`
`Cps
`
`

`

`438
`
`A. Mihranyan et al. / International Journal of Pharmaceutics 269 (2004) 433–442
`
`LCC
`
`Algiflor
`
`AMC
`
`Cladophora
`
`35
`
`30
`
`25
`
`20
`
`15
`
`10
`
`5
`
`0
`
`35
`
`30
`
`25
`
`20
`
`15
`
`10
`
`5
`
`0
`
`Moisture content, %
`
`Moisture content, %
`
`0
`
`20
`
`40
`
`60
`
`80
`
`100
`
`Relative humidity, %
`
`MCC
`
`35
`
`30
`
`25
`
`20
`
`15
`
`10
`
`5
`
`0
`
`Moisture content, %
`
`0
`
`20
`
`40
`
`60
`
`80
`
`100
`
`Relative humidity, %
`
`Fig. 3. Moisture sorption isotherms for cellulose powders of varying crystallinity. The lower curve represents adsorption and the upper
`curve desorption.
`
`

`

`A. Mihranyan et al. / International Journal of Pharmaceutics 269 (2004) 433–442
`
`439
`
`100% H
`
`96% RH
`
`75% RH
`
`40% RH
`11% RH
`
`40
`
`35
`
`30
`
`25
`
`20
`
`15
`
`10
`
`05
`
`Moisture content, %
`
`40
`
`50
`
`60
`
`70
`
`80
`
`90
`
`100
`
`Crystallinity index, %
`
`Fig. 4. Moisture content vs. crystallinity of cellulose powders. Lines are drawn as guides for the eye. Note that, for clarity, RH 25 and
`63% are omitted.
`
`monotonic decrease with increased crystallinity was
`no longer observed.
`
`3.4. Surface area and porosity
`
`The surface area values and the pore volumes are
`presented in Table 1. The BET N2 surface area of
`
`the Cladophora cellulose powder exceeded the corre-
`sponding values of the other samples manifold. Also
`the pore volume of Cladophora cellulose powder was
`found to be significantly larger than for the other cel-
`lulose samples. For all cellulose powders except from
`the Cladophora cellulose sample, the BET H2O sur-
`face was much larger than that obtained using N2.
`
`Table 1
`Primary characteristics of cellulose powders
`
`4. Discussion
`
`Crystallinity
`index (%)
`
`LCC
`AMC
`MCC
`Algiflor
`Cladophora
`
`45.0
`69.1
`82.2
`81.7
`95.2
`
`Surface area
`
`N2
`(m2/g)
`0.48
`1.13
`0.96
`5.76
`94.7
`
`H2O
`(m2/g)
`204.2
`168.3
`117.3
`130.6
`52.80
`
`Pore volume
`(cm3/g)
`
`0.00163a
`0.00441b
`0.0030c
`0.0250d
`0.5540e
`
`a Total volume of pores filled with nitrogen at a relative partial
`pressure of 0.9861.
`b Total volume of pores filled with nitrogen at a relative partial
`pressure of 0.9857.
`c Total volume of pores filled with nitrogen at a relative partial
`pressure of 0.9862.
`d Total volume of pores filled with nitrogen at a relative partial
`pressure of 0.9858.
`e Total volume of pores filled with nitrogen at a relative partial
`pressure of 0.9799.
`
`Various methods, such as grinding, swelling, and
`extraction, were used to induce crystallinity changes.
`The chemical treatment was found to be the most
`efficient way to obtain low crystallinity cellulose.
`Extraction of cellulose from green algae produced
`a higher crystallinity material than extraction from
`brown algae. Not only were materials different in their
`crystallinity but also in their surface texture. Interest-
`ingly, the Cladophora cellulose sample was composed
`of numerous intertwined strings, which produced an
`aggregate web-like structure of high porosity and
`large surface area. It should be noted that SEM mi-
`crographs of the Cladophora cellulose particles taken
`previously (Strømme et al., 2002) were of lower
`magnification (10,000×); hence, fine texture of the
`Cladophora cellulose particles was not clearly visible.
`
`

`

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`
`A unique combination of high porosity, surface area,
`and crystallinity distinguishes Cladophora cellulose
`powder from any other cellulose hitherto reported.
`The main task of this paper was to investigate how
`the material’s structure affected the moisture sorption
`process. The results of this study revealed direct rela-
`tionship between crystallinity and extent of moisture
`sorption at RHs below 75%: the lower crystallinity
`of the powder, the higher moisture content. At higher
`RHs, a sudden increase in the moisture sorption of the
`Cladophora cellulose sample was observed. A similar
`increase has been observed earlier in very porous cel-
`luloses and was then ascribed to capillary condensa-
`tion in the pore network (Matsumoto et al., 1998). A
`comparison between the pore volume obtained by the
`BET N2 adsorption analysis of the Cladophora cellu-
`lose powder (0.554 cm3/g) and the amount of water
`adsorbed at 100% RH (0.350 cm3/g) shows that the
`observed increase is related to pore network filling.
`It could also be noticed that, even though present
`in all samples, the hysteresis loop may have different
`origins for the different samples. The hysteresis loops
`at high relative pressures are often identified in highly
`porous materials (Sing et al., 1985). They usually arise
`
`due to differences in condensation and evaporation oc-
`curring in pores with narrow necks and wide bodies,
`i.e. “ink bottle” pores, or due to differences of menisci
`during adsorption and desorption in cylindrical pores
`(Cohan, 1938). The presence of hysteresis at low rel-
`ative pressures is associated with swelling or some
`other kind of interaction between the sorbate and sor-
`bent in the bulk (Sing et al., 1985). Thus, the hystere-
`sis loop observed in the moisture sorption isotherm
`of the Cladophora cellulose sample is likely to arise
`due to the porous texture of this material, whereas in
`the rest of materials the hysteresis arises mainly due
`to absorption in the bulk of cellulose particles. Fur-
`thermore, the lower the degree of cellulose order, the
`broader is the hysteresis.
`Fig. 5 illustrates the surface area available for mois-
`ture sorption as a function of crystallinity. Accord-
`ing to contemporary understanding of the cellulose
`structure, cellulose particles are aggregates composed
`of coaxial fibrils with abundant fibril-to-fibril contact
`surfaces (Wickholm et al., 1998). When adsorbed on
`the fibrilar contact surfaces, water molecules cause
`swelling and thus further exposure of the bulk (Fig. 6).
`The ability of water to penetrate the structure and
`
`
`
`20
`
`40
`
`60
`
`80
`
`100
`
`Crystallinity index, %
`
`250
`
`200
`
`150
`
`100
`
`50
`
`0
`
`0
`
`Surface area available for moisture sorption, m2/g
`
`Fig. 5. Surface area vs. crystallinity of cellulose powders. The line is drawn as a guide for the eye.
`
`

`

`A. Mihranyan et al. / International Journal of Pharmaceutics 269 (2004) 433–442
`
`441
`
`Fig. 6. Schematic representation of vapor sorption by cellulose.
`
`cause swelling will depend on the number of available
`hydroxyl groups or, in other words, degree of crys-
`tallinity (Verlhac et al., 1990). Since gases such as N2,
`Kr, or Ar, which are commonly used for BET gas ad-
`sorption, do not specifically interact with cellulose, the
`surface area available for their sorption will be limited
`to the outer surface of the aggregates only. This is why
`the surface area values obtained with BET H2O are
`orders of magnitude larger than those obtained with
`N2 for all the cellulose powders in this study except
`from the highly crystalline Cladophora cellulose.
`
`5. Conclusions
`
`This study showed that moisture sorption in cellu-
`lose is a complex process directly associated with, and
`controlled by, the structural properties of cellulose,
`such as surface area, pore volume, and crystallinity.
`The extent of moisture sorption was shown to decrease
`with increasing crystallinity of the samples at relative
`humidities below 75%. At higher relative humidities,
`filling of the large pore volume of the Cladophora cel-
`lulose accounted for the observed increase in mois-
`ture content. In conclusion, the structure of cellulose
`should be thoroughly considered when manufacturing
`low moisture grades of MCC.
`
`Acknowledgements
`
`This study was part of a research program in
`Pharmaceutical Materials Science at Uppsala Univer-
`
`sity. One of the authors (M.S.) is a Royal Swedish
`Academy of Sciences (KVA) Research Fellow and
`would like to thank the Academy for their support.
`The Swedish Foundation for Strategic Research (SSF)
`is also acknowledged for their support to our multi-
`disciplinary research in materials physics and phar-
`maceutics. The Swedish Institute is acknowledged
`gratefully for the scholarship provided to one of the
`authors (A.M.).
`
`References
`
`Ahlneck, C., Alderborn, G., 1988. Solid state stability of
`acetylsalicylic acid in binary mixtures with microcrystalline
`and microfine cellulose. Acta Pharm. Suec. 25, 41–52.
`Ahlneck, C., Zografi, G., 1990. The molecular basis of moisture
`effects on the physical and chemical stability of drugs in the
`solid state. Int. J. Pharm. 62, 87–95.
`Amidon, G.E., Houghton, M.E., 1995. The effect of moisture on
`the mechanical and powder flow properties of microcrystalline
`cellulose. Pharm. Res. 12, 923–929.
`for direct
`Bolhuis, G.K., Chowhan, Z.T., 1995. Materials
`compaction. In: Alderborn, G., Nyström, C. (Eds.), Pharma-
`ceutical Powder Compaction Technology. Marcel Dekker, Inc.,
`New York, pp. 428–440.
`Brunauer, B., Emmett, P.H., Teller, E., 1938. Adsorption of gases
`in multimolecular layers. J. Am. Chem. Soc. 60, 309–319.
`Carstensen, J.T., Lothari, R.C., 1983. Solid-state decomposition of
`alkoxyfuroic acids in the presence of microcrystalline cellulose.
`J. Pharm. Sci. 72, 1149–1154.
`Carstensen, J.T., Osadca, M., Rubin, S.H., 1969. Degradation
`mechanisms for water soluble drugs in solid dosage forms. J.
`Pharm. Sci. 58, 549–553.
`Cohan, L.H., 1938. Sorption hysteresis and the vapor pressure of
`concave surfaces. J. Am. Chem. Soc. 60, 433–435.
`
`

`

`442
`
`A. Mihranyan et al. / International Journal of Pharmaceutics 269 (2004) 433–442
`
`Doelker, E., Massuelle, D., Veuillez, F., Humbert-Droz, P., 1995.
`Morphological, packing, flow and tabletting properties of new
`Avicel types. Drug Dev. Ind. Pharm. 21, 643–661.
`Ek, R., Gustafsson, C., Nutt, A., Iversen, T., Nyström, C., 1998.
`Cellulose powders from Cladophora sp. algae. J. Mol. Recognit.
`11, 263–265.
`European Pharmacopoeia, 2002, 4th ed. Strasbourg.
`Genton, D., Kesselelring, U.W., 1977. Effect of temperature and
`relative humidity on nitrazepam stability in solid state. J.
`Pharm. Sci. 66, 676–680.
`Howsman, J.A., 1949. Water sorption and the poly-phase structure
`of cellulose fibers. Textile Res. J. 19, 152–162.
`Matsumoto, K., Nakai, Y., Oguchi, T., Yamamoto, K.Y., 1998.
`Effect of pore size on the gaseous adsorption of ethenzamide on
`porous crystalline cellulose and the physicochemical stability
`of ethenzamide after storage. Chem. Pharm. Bull. 46, 314–
`318.
`Nyqvist, H., 1983. Saturated salt solutions for maintaining specified
`relative humidities. Int. J. Pharm. Tech. Prod. Mfr. 4, 47–48.
`Patil, N.B., Dweltz, N.E., Radhakrishnan, T., 1965. Studies on
`decrystallization of cotton. Textile Res. J., 517–523.
`Segal, L., Creely, J.J., Martin Jr., A.E., Conrad, C.M., 1959. An
`empirical method for estimating the degree of crystallinity of
`native cellulose using the X-ray diffractometer. Textile Res. J.,
`786–794.
`Sing, K.S.W., Everett, D.H., Haul, R.A.W., Moscou, L.,
`Pierotti, R.A., Rouquerol, J., Siemienewska, T., 1985. Repo-
`
`rting physisorption data for gas/solid systems with special
`reference to the determination of surface area and porosity
`(recommendations). Pure Appl. Chem. 57, 603–619.
`Strømme, M., Mihranyan, A., Ek, R., 2002. What to do with all
`these algae? Mater. Lett. 57, 569–572.
`Stubberud, L., Arwidsson, H.G., Larsson, A., Graffner, C., 1996.
`Water solid interactions II. Effect of moisture sorption and glass
`transition temperature on compactability of microcrystalline
`cellulose alone or in binary mixtures with polyvinyl pyrolidone.
`Int. J. Pharm. 134, 79–88.
`Suzuki, T., Nakagami, H., 1999. Effect of crystallinity of
`microcrystalline cellulose on the compactability and dissolution
`of tablets. Eur. J. Pharm. Biopharm. 47, 225–230.
`Verlhac, C., Dedier, J., Chazny, H., 1990. Availability of surface
`hydroxyl groups in Valonia and Bacterial cellulose. J. Polym.
`Sci.: Part A: Poly. Chem. 28, 1171–1177.
`Wefers, K., 1964. Morphologie und Eigenschaften von kalziniertem
`Aluminiumhydroxid. Erzmetall XVII, 583–636.
`Wickholm, K., Larsson, P.T., Iversen, T., 1998. Assignemnt of
`non-crystalline forms in cellulose I by CP/MAS 13C NMR
`spectroscopy. Carbohydr. Res. 312, 123–129.
`Zografi, G., Kontny, M.J., 1986. The interactions of water with
`cellulose and starch-derived pharmaceutical excipients. Pharm.
`Res. 3, 187–194.
`Zografi, G., Kontny, M.J., Yang, A.Y.S., Brenner, G.S., 1984.
`Surface area and water vapor sorption of microcrystalline
`cellulose. Int. J. Pharm. 18, 99–116.
`
`