Adsorption of some drugs on microcrystalline cellulose in aqueous solution

Adsorption of some drugs on microcrystalline cellulose in aqueous solution

Ville Matilainen
Seminar 30.11.2006
I. Literature review

1. Introduction

There are not so many studies about adsorption of microcrystalline cellulose (MCC) onto drugs although MCC is widely used as a pharmaceutical excipient. In terms of tableting technology, the material is described as a filler or binder in that it is usually added to formulations to enhance The adsorption of a drug onto solid dosage form excipients may influence its characteristics, analytical testing and bioavailability. Adsorption is one of the most important mechanisms of interaction between drugs and excipients. This is particularly important for drugs which are normally used in low doses. Drug interactions are one of the most important factors that should be considered in any preformulation study (Al-Nimry et al.1997). Adsorption is a formation of a layer of gas, liquid, or solid on the surface of a solid or, less frequently, of a liquid. There are two types depending on the nature of the forces involved. In chemisorption a single layer of molecules, atoms, or ions is attached to the adsorbent surface by chemical bonds. In physisorption adsorbed molecules are held by the weaker van der Waal´s forces. Adsorption is an important feature of surface reactions, such as corrosion, and heterogeneous catalysis. The property is also utilized in adsorption chromatography. 2. Adsorption

Adsorption is a process in which molecules from gas or liquid phase land on, interact with and attach to solid surfaces. The reverse process of adsorption, i.e. the process n which adsorbed molecules escape from solid surfaces, is called desorption. Adsorption onto a surface is divided into two different types: physical adsorption and chemical adsorption. Shorter term for chemical adsorption is chemisorption and for physical adsorption is physisorption. Major differences between these two are shown at table (Table 1.). Table 1. Comparison on of physical and chemical adsorption (Atkins P.W. 1994) physical adsorption Heat released on adsorption less than Heat of adsorption greater than about 40 kJ mol-1 about 80 kJ mol-1 adsorption only at temperatures less Adsorption can occur at high temperatures than the boiling point of the adsor- bate (the material being adsorbed) Multilayer adsorption occurs At most, monolayer can form No activation energy involved in the Activation energy may be involved adsorption process Extent of adsorption is mostly Extent of adsorption depends on both dependent adsorbate and adsorbent on properties of the adsorbent (the material doing the adsorbing) Adsorption occurs when temperature Adsorption occurs when temperature is high is low There is a van der Waals interaction between the adsorbate and the substrate in physisorption (Atkins P.W 1994). Van der Waals interactions have a long range but are weak and the energy released when a particle is physisorbed is of the same order of magnitude as the enthalpy of condensation. Such small amounts of energy cam be adsorbed as vibrations of the lattice and dissipated as thermal motion and a molecule bouncing across the surface will gradually lose its energy and finally adsorb to it in the process called accommodation. In chemisorption the particles stick to the surface by forming a chemical bond and tend to find sites that maximize their coordination number with the substrate (Atkins P.W 1994). The enthalpy of chemisorption is greater than enthalpy of physisorption. A chemisorbed molecule may be torn part at the demand of molecular fragments on the surface as a result of chemisorption is one reason why The enthalpy of adsorption depends on the extent of surface coverage, mainly because the adsorbate particles interact. If the particles repel each other the enthalpy of adsorption becomes less exothermic as coverage increases. If the adsorbate particles attract each other then they tend to cluster together in islands and growth occurs at borders. These adsorbates also show order-disorder transitions when they are heated enough for thermal motion to overcome the particle-particle interactions but not so much that they are desorbed (Atkins P.W. 1994). There are several factors which will affect the extent of adsorption from solution (Aulton M. E 2000). These are solute concentration, temperature, value of pH and surface area of adsorbent. When solute concentration increases, it will cause an increase in the amount of adsorption that occurs at equilibrium until a limiting value is reached. Adsorption is generally exothermic and hence an increase in temperature leads to decrease in adsorption. The influence of pH is usually through a change in the ionization of the solute and the influence will be depending on which species is more strongly adsorbed. An increased surface area achieved by a reduction in particle size or the use of a porous material will increase the extent of adsorption. The phenomenon of adsorption from solution finds practical application of pharmaceutical interest in chromatographic techniques and in the removal of unwanted materials. In addition adsorption may give rise to certain formulation problems. 2.1 Adsorption isotherms

Adsorption equilibrium data is typically plotted in the form of an adsorption isotherm (i.e. at constant temperature) with the mass adsorbed on the y-axis and the mass in the fluid on the x-axis. The shape of the curve is significant and factors heavily into design. "Favourable" isotherms permit higher solid loadings at lower solution concentrations. These tend to start out steep and level out. Isotherms which start out flat are "unfavourable", since they only work well at high concentrations of solute. Usually, as temperature increases the amount adsorbed decreases (permitting thermal Figure 1. Classification of isotherms for the adsorption of vapours by solids. Ordinates x/m, Five types of physisorption isotherms are found over all solids (Figure 1.). Type I is found for porous materials with small pores. It exhibits a rapid rise in adsorption up to a limiting value. Type II is for non-porous materials and type III porous materials with cohesive force between adsorbate molecules greater than the adhesive force between adsorbate molecules and adsorbent. Type IV is staged adsorption (first monolayer then build up of additional layers). Type V porous materials with cohesive force between adsorbate molecules and adsorbent being greater than that between 2.1.1 Freundlich isotherm

The Freundlich isotherm is purely empirical isotherm. It has nevertheless proven to be a useful tool in the evaluation of drug adsorption onto tablet excipients. Freundlich isotherm fits data that correspond to type I Adsorption. This isotherm is used in describing the adsorption of solute from a where X is the amount of substance adsorbed, m is the amount of adsorbent. K and n are constants, K gives an approximate measure of relative adsorbent capacity for given drug while n gives general idea about affinity of the adsorbate for the adsorbent (Freundlich 1926). C is the amount of residual 2.1.2 Langmuir isotherm

Irving Langmuir devised a simple model involving a thermodynamic equilibrium to predict the fraction of solid surface covered by an adsorbate as a function of its gas pressure. This was later extended to liquid systems, where the equilibrium involved concentrations in solution. In this model adsorbate and solvent molecules compete to adsorb on sites on the the surface of the powder. Each site must be occupied by either a solvent molecule or an adsorbate molecule. Langmuir isotherm is a model for the adsorption process which forms only a monolayer. The model is valid for most chemisorption process and for type I adsorption process. There is some basic assumption for Langmuir isotherm. First molecules are adsorbed on fixed number of localized sites. Second each site can only hold one adsorbate molecule. Third all sites are energetically equivalent. Fourth there are no adsorbate-adsorbate interactions. where x is amount of drug adsorbed by amount of adsobent. P is equilibrium pressure for a given amount of substance adsorbed. a and b are constants. b the limiting adsorptive capacity, a is used as a measure of the relative affinity of the adsorbate for the adsorbent (Langmuir I 1916). 2.1.3 BET isotherm

The Brunauer, Emmett, and Teller (BET) equation also assumes the adsorbent surface is composed of fixed individual sites. However, the BET equation (eq. 3) assumes that moleculescan be adsorbed more than one layer thick on the surface of the adsorbent. The BETequation assumes that the energy required to adsorb the first particle layer is adequate to hold the monolayer in place. BET equation fits reasonably well all known adsorption isotherms observed so far (types I to V) for various types of solid. BET- isotherm assumption is same as Langmuirs but BET- isotherm allows where P is equilibrium pressure and P0 is saturate vapour pressure of the adsorbed gas at the temperature. P/P0 is called relative pressure. V is volume of adsorbed gas per kg adsorbent and Vm is volume of monolayer adsorbed gas per kg adsorbent. C is constant associated with adsorption heat and with condensation heat (Brunauer S et al. 1938). 3. Microcrystalline cellulose

MCC is white, tasteless, free flowing powder. It is insoluble in water, dilute acids, and most organic solvents. It is also practically insoluble in sodium hydroxide. It exhibits properties as an excipient for solid dosage forms. It compacts under minimum compression pressures, has high binding capability, and creates tablets that are extremely hard, stable, yet disintegrate rapidly. Other advantages include low friability, inherent lubricity, and the highest dilution potential of all binders. MCC is basically cellulose and is derived from high quality wood pulp. MCC can only be derived from a special grade of alpha cellulose. One of the few problems associated with MCC, however, is its poor flowability. Using a larger particle size MCC could provide better flowability to a limited extent, and granulation is often recommended when MCC is used in tablet formulation. The results showed that the products of MCC codried with β-cyclodextrin significantly improved the flowability of MCC powder.(Tsai et Cellulose is a polysaccharide made up of monomeric glucose residues forming a linear polymer chain. It is fibrous, tough and water insoluble unbranched homopolysaccaride of 10 000 or more glucose units connected by a 1-4 glycosidic bond. These 1-4 bonds are in β configuration as a result of which the D-glucose chain assumes an extended conformation and undergoes side by side aggregation into insoluble fibrils. Linear chains of cellulose in the fibrils are held together by cross links of large number of hydrogen bonds. (Biswas and Chattoraj 1997). Fpreparation of direct-compressed tablets (Okada et al. 1987). MCC is also essential excipient for extrusion-spheronization. MCC aids the spheronization process by absorbing water like a molecular sponge and helps in the binding and lubrication of the moisture powder mass during extrusion (Fielden et al. 1988). MCC is extrudable at a wide range of water content, but the quality of the re- sulting products varies (Fechner et al. 2003). 3.2 Microcrystalline cellulose and water

The use of MCC as a tablet excipient is widespread in the pharmaceutical field. Interaction between MCC and water is a critical issue in formulation, processing and product performance of solid pharmaceutical dosage forms such as tablets and beads. MCC is insoluble hydrophilic polymer that’s why it can take up considerable amounts of water (Agrawal et al. 2004). Zografi et al. studied surface area and water vapour sorption of MCC. In the MCC itself can be found water. In their research they found that water is existing at least three thermodynamic states in MCC. They are tightly bound, relatively unrestricted and in an intermediate state (Zografi et al. Moisture in MCC may cause stability problems for moisture sensitive drugs. Mihranyan et al. studied in their research the influence of crystallinity and surface area on uptake of moisture in cellulose powders. Ordinary MCC is manufactured with 4-5% (w/w) moisture content. Results of the study indicated that moisture sorption in cellulose complex is a pomplex 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 crystallinty of the samples at relative humidities below 75%. (Mihranyan et al. 2004) Sorption of water adds mass to the MCC solid. It also increases the free volume of molecules by distributing hydrogen bond interactions between cellulose chains. Changes in both mass and volume can affect the true density of MCC. True density of MCC is also dependent of water content. True density of MCC increases initially with increasing water content but decreases when water content is further increased. This suggests that initially gain in weight overcomes gain in volume but the reverse is true when more than 5% of water is adsorbed. The latter gradual decrease in MCC true density is consistent with the swelling propensity of words at high humidities. (Sun 3.3 MCC and drug

Although MCC has been widely used in the field of drug formulations, not so many studies have been undertaken to clarify the interaction of drugs with MCC. The fact is that the interaction type may depend to a certain extent on the properties of the components, method of activation and other If MCC is composed of clusters of pure cellulose microcystals, adsorption of drugs or other low- low molecular adsorbates would be slight. However, since appreciable amorphous regions in the microcrystallites, considerable amounts of drugs can be adsorbed at these regions. As for dye adsorption to cellulosic fiber, it is considered that fairly large dyes cannot penetrate between fibers arranged in a regular close –spaced array. Cationic drugs are adsorbable on the surface by an ion. exchange mechanism, due to negatively charged microcrystalline surface. Penetration of the drugs into the intermicellar space of microcrystallites may also be important in the adsorption. (Okada et Drug concentration effects also on adsorption. This is because more drug molecules will be available for adsorption at higher concentrations than at lower ones. (Al-Nimry et al. 1997) An increase in temperature decreases adsorption of drug to MCC. This indicates that the adsorption process is exothermic in nature. This is because the molecules of drug tend to adsorb at the solid surface of the insoluble excipient in order to become energetically more stable. An increase in temperature shifts the adsorption reaction backwards and decreases the amount adsorbed per gram Some studies have indicated that adsorption increases when pH of the solution increases (Al-Nimry et al. 1997, Okada et al. 1987, El-Samaligy et al. 1986 , Franz and Peck 1982). This is attributed to the reduction of the solubility of the drug with the increase in pH (Al-Nimry et al. 1997). Franz and Peck suggested that it is due to the ionization of carboxyl groups on the cellulose surface. When the pH values of the suspensions are increased, the number of negatively charged carboxylate groups on the surface of the MCC particles increases. The increased number of anionic surface sites leads to increased adsorption of predominantly positively charged drugs at surface of particles. Franz and Peck also suggested that the possibility also excist that these hydrophobic drugs are adsorbed from solution as the nonprotonated free bases (Franz and Peck 1982). On the other hand, adsorption decreases with increase of ion strength (Okada et al.1987, Franz and Peck 1982). But this is also depended on the pH of the suspension. At high pH values an increase added ionic strength causes a decrease in the amount of drug adsorbed. At low pH values, where the cellulose carboxy groups are predominantly in their nonionized form, an increase in added ionic strength causes a slight increase in the amount of drug adsorbed by a particular type of MCC. II. Experimental part
4. Aim of the study

Because MCC is important excipient in pharmaceutical field, it was chosen as an excipient for this study. Studied drugs were picked with help of literature. Basic idea was to find drugs, which adsorb differently with MCC. Previous studies indicated that ethacridin lactate adsorbed strogly on MCC and lidocaine hydrochlorid slightly. Other local anaesthetics were chosen because structures were similar to lidocaine hydrochlorid. Caffeine and sodium salicylate were chosen because they had different chemical structure than others. Also the idea was to see if the results could be fitted into Langmuir and Freundlich isotherms. Results were also compared to previous results, which could 5. Adsorption experiment

Adsorption between MCC and the drugs were tested. Experiments were made several times to see if the experiment process was valid. Corrected absorbance was calculated subtracting absorbance of the sample from absorbance of MCC. Difference of amounts of MCC and possible dilution were taken in account in these calculations. Amounts of bonded and free drug were calculated with help of corrected absorbance. This could be made if the correlation coefficient of calibration curve indicated good linearity. Amount of the free drug was calculated multiplying amount of the free drug in the stock solution and corrected absorbance of sample and dividing this with absorbance of the stock solution. Amount of bonded drug was calculated subtracting free drug in the stock solution and free drug in the sample system. Dividing bonded drug and amount of used MCC gave a result which indicated how strong adsorption was between tested drug and MCC. Adsorption isotherms are shown in figure (Figure 2) Das Gupta and Pramar wrote in their article Quatitation of scopolomani hydrobromide when adsorbed onto MCC and sodium carboxymethylcellulose in tablets, that hydrochloride caused ionization of lidocaine (Das Gupta and Pramar). Ionization of lidocaine makes it more affinitive towards MCC when adsorption happens. This was the reason why all hydrochloride, which were tested, adsorbed onto MCC. Ethacridin lactate was one of the drugs that Okada et al. tested in their research. (Okada et al.). Since MCC has carboxyl groups on its surface, it should act as a weakly acidic cationexchager above pH4. In their research, they also tested cation-exchage properties of MCC. Results were that with other drugs (chlorpromazine(CPZ), triflupromazine and promazine) the pH values gradually decrease with increase of salt concentrations except in ethachridin lactate- MCC system. This indicated that H+ is released from the MCC surface by cation- exchange of Na+, K+ or CPZH+. Okada et al. found out that non-electrostatic forces involved in the adsorption might be hydrogen bonding and van der Waals forces. Figure 2. Adsorption isotherm curves for caffeine, cinchocaine HCl, ethacridin lactate, lidocaine HCl, procaine HCl, sodium salicylate and tetracaine HCl 5.1 Caffeine
Results indicate that there is a slight adsorption between caffeine and MCC. Chemical structure of caffeine (C8H10N4O2) is the reason why adsorption is so low. It doesn’t form strong bonds with MCC. Caffeine was also studied with low concentrations to see adsorption. Although repeatability of experiment was not good, differences between the experiments were slight. Reasons might be unsuccessful filtrarion or measurement errors. Caffeine was not fitted into either Langmuir or Freundlich isotherm because regression coefficient for both was around 0.80.
5.2 Cinchocaine hydrochloride
Results indicated that there was adsorption between MCC and cinchocaine hydrochloride. With 3g
of MCC, half of the drug was adsorbed. With 7g of MCC 2/3 of drug were adsorbed. This indicates that binding sites of MCC are getting full and that’s why adsorption index is not as great as with 3g. Adsorption isotherm shows that experiment process was valid. Curves are quite similar. Cinchocaine HCl adsorbs on MCC quite well. Previous studies where cinchocaine HCl adsorbs on MCC were not found. Experiment results were fitted on Langmuir and Freundlich isotherm. The correlation coefficients indicate that Freundlich isotherm is better cinchocaine HCl. 6.3.3 Ethacridin lactate

Adsorption of ethacridin lactate on MCC was quite large. On the first experiment concentrations were higher than on the second experiment. Shapes of the adsorption isotherm curves were similar which indicate that experiment process was valid (Figure 2). Okada et al. discovered that adsorption isotherms for ethacridin lactate appeared to be not of Langmuir type but of Freundlich type. Further, the relatively low value of 1/n for Ethacridin lactate- MCC indicates that the adsorption isotherm is moderately curved with increasing drug concentration, and shows some similarity to Langmuir- type adsorption. They also wrote that in the work of El-Samaligy et al. on the adsorption of antibiotics on MCC the adsorption was assumed to be of Langmuir type though the saturated adsorption region was not clearly shown in their adsorption isotherms (El-Samaligy). Thus the adsorption can probably also be described by a Freundlich type equation. Since the intermediate part in langmuir type adsorption can usually be approximated by Freundlich type adsorption. The possibility that the present adsorption isotherms represent a Langmuir type adsorption cannot be ruled out completely. Adsorption isotherm curve in this experiment at lower concentration looks like Langmuir-type (Aulton M.E.) (Figure 1.) Curve rises rapidly up to a limiting value. Value of correlation coefficient (R2) was slightly better when lower concentrations were studied. Values indicate that acrinol is Langmuir type isotherm. Constants were calculated and there was a difference on them. k2 tells maximum adsorbent capacity and constant k represents the affinity constant. 6.3.4 Lidocaine hydrochloride

Results indicated that there is adsorption between MCC and lidocaine hydrochloride but it is not so strong. Das Gupta and Pramar found out in their research that lidocaine hydrochloride adsorbed onto MCC. Comparing the results is not possible due to different kind of experiment process. Although one thing can be said, lidocaine hydrochloride adsorbs onto MCC. With 10g of MCC most of the drug was adsorbed on MCC. Adsorption isotherm of lidocaine hydrochloride on MCC is shown in figure (Figure 2). Curves of it indicate that there is lidocaine hydrochloride adsorbs on MCC. Pramar and Das Gupta discovered also this in their research (Pramar and Das Gupta). Langmuir isotherm described better adsorption of lidocaine HCl on MCC. Regression coefficients were 0.89 which is not real good but for Freundlich isotherm it was even worse. 6.3.5 Procaine hydrochloride

Results indicated that there is adsorption between drug and the additive. Adsorption is strong because half of the drug is adsorbed when there is 1 g of MCC in the system. It can be seen from adsorption isotherm curves (Figure 2). Curves look quite similar and shape looks a bit same with lidocaine HCl. Procaine HCl was fitted better in Freundlich isotherm due to better regression 6.3.5 Sodium salicylate

Adsorption of this drug was not so great although it’s in ionized form in stock solution. Okada et al. wrote in their article that Na+ should adsorb on MCC like it was mentioned above. Results indicate that there was only very slight adsorption on MCC. Reason could be that sodium salicylate didn’t ionized well enough. Used drug was also quite old almost 15 years that might also be reason for this. Perhaps chemical structure had been changed during the storage time. Sodium salicylate adsorbed slightly on MCC. From the curve can be seen that when the concentration is higher adsorption rises rapidly (figure 2). Sodium salicylate didn´t fit either Langmuir isotherm or Freundlich isotherm due to low regression coefficient. Better results might have been with higher concentrations but then comparing to other drugs would have been difficult. 6.3.6 Tetracaine hydrochloride

Results show that there is adsorption between tetracaine hydrochloride and MCC. Adsorption is strong because 1 g of MCC adsorbs half of the drug. Adsorption isotherm curves indicate that tetracaine HCl adsorbs on MCC (Figure 2). Adsorption is not as strong as in the case of ethacridin lactate. Curves of lidocaine HCl, procaine HCl and tetracaine HCl are quite similar. Adsorption experiment results were fitted in Langmuir and Freundlich isotherms. The correlation coefficient on Freundlich isotherm was better than Langmuir isotherms. 7. Conclusions

Because MCC is widely used as an excipient in pharmaceutical industry, it is important to study also adsorption between MCC and drugs. Some of the drugs, which were tested, are not used a solid dosage form so for them it’s not so important to know adsorption. Comparing to past results was difficult due to lack of literature. Only two articles were found where they had studied same things Every drug was compared to ethacridin lactate because it was strongly adsorbed. From figure can be seen that all hydrochlorides are approximately same at low concentrations (figure 2). Drug/MCC index is different with hydrochlorides when concentration increases. Caffeine and sodium salicylate does not adsorb so much. Results indicate that ethacridin lactate had strong adsorption on MCC like Okada et al. had found out in their research. All the hydrochlorides had had also adsorption. Das Gupta and Pramar had found it for lidocaine HCl. Different chemical structure of these drugs didn’t affect on adsorption process. Mostly adsorption of these drugs was due to hydrochloride group of the drug. Results are not good enough as can be seen from adsorption isotherm curves. They were no similar every time and they were only repeated twice. This might be due to measurement errors and filtration errors. Generally from the results can be seen which of the tested drugs have adsorption and the similarity of hydrochlorides. Because results were not clear, further studies are References
Agrawal A, Manek RV, Kolling W, Neau SH: Water distribution studies within microcrystalline
cellulloseand chitosan using differential scaning clorimetry and dynamic vapour sorption analysis.
J.Pharm. Sci 93:1766-1778, 2004
Al-Nimry S, Assaf S, Jalal I, Najib N: Adsorption of ketotifen onto some pharmaceutical excipients.
Int. J. Pharm. 149:115-121, 1997
Aulton ME: Pharmaceutics The science of dosage form design. 58-61, 616-628, Churchill
Livingstone, London, 2000
Atkins PW: Physical chemistry, p.986-993 5ed. Oxford university press, Oxford, 1994
Biswas SC and Chattoraj DK: Polysaccaride-surfactant interaction. 1. Adsorption of cationic
surfactants at the cellulose water interface. Langmuir 13:4595-4511, 1997
Brunauer S, Emmett P H, Teller E: Adsorption of gases in multimolecular layers.
J. Am. Chem. Soc. 60:309-319, 1938

Edge S, Steele FD, Chen A, Tobyn MJ, Staniforth J.N: The mechanical properties of compacts of
microcrystalline cellulose and silified MCC. Int. J. Pharm. 200:67-72, 2000
El-Samaligy MS, El-Mahrouk GM, El-Kirsh TA: Adsorption-desorption effect of microcrystalline
cellulose on ampicillin and amoxycillin. Int. J. Pharm. 31:137-144 1986
Fechner P, Wartewig S, Füting M, Heilmann A, Neubert R, Kleinebudde P. Properties of
microcrystalline cellulose and powder cellulose after extrusion/spheronization as studied by fourier
transform Raman spectroscopy and environmental scanning electron microscopy. AAPS PharmSci.
5:1-13, 2003
Franz RM, Peck GE: In vitro adsorption –desorption of fluphenazine dihydrochloride and
promehazine hydrochloride by microcrystalline cellulose. J. Pharm. Sci. 71:1193-1199, 1982
H. Freundlich: Colloid and Capillary Chemistry, translated from the 3rd German Edn. by H.S.
Hatfield, Methuen, London 1926
I. Langmuir: Constitution and fundamental properties of solids and liquids. J. Am. Chem. Soc., 38:
2221-95, 1916
Mihranyan A, Llgostera AP, Karmhag R, Strømme M, Ek R: Moisture sorption by cellulose powder
of varying crystallinity. Int. J. Pharm. 269:433-442 2004
Muratova SA, Burkhanova ND Yagai SM, Nikonovich GV, Pulatova Kh, Rashidova S: Studying
interactions in microcrystalline-drug systems. Pharm Chem. J. 36:619-621, 2002
Okada S, Nakahara H, Isaka H: Chem.Pharm.Bull., 35:761-768, 1987
Pramar Y, Das Gupta V: Quatitation of scopolamine hydrobromide when adsorbed onto MCC and
sodium carboxymethylcellullose tablets. Drug Dev. Ind. Pharm. 17:2401-2407, 1991
Rivera S, Ghodbane S: In vitro adorption-desorption of famotidine on microcrystalline cellulose.
Int. J. Pharm. 108:31-38, 1994
Steele D, Edge S, Tobyn M, Moreton R, Staniforth J: Adsorption of amine drug onto
microcrystalline cellulose and silified microcrystalline cellulose samples. Drug Dev. Ind. Pharm.
29:475-487, 2003
Sun C: True density of microcrystalline cellulose. J. Pharm. Sci. 94:2132-2134, 2005
Tsai T, Wu J-S, Ho H-O, Sheu M-T: Modification of physical characteristics of microcrystalline
cellulose by codrying with β-cyclodextrins. J Pharm. Sci. 18:117-122, 1997
Zografi G, Kontny MJ, Yang AYS, Brenner GS: Surface area and water vapour sorption of MCC.
Int. J. Pharm. 18:99-116, 1984

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