Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5428_Библиотеки_им_академика_М_И_Перельмана
.pdf
represents the force required to maintain sliding between two surfaces
100-102
. Thus, µ 1 and µ
2
can be expressed as;
img
There are different theoretical models that describe the mechanical strength of tablets.
Solubility
The phenomenon of the solubility of a substance in another liquid is of great importance in
chemistry and has wide application in various fields including pharmaceutical technology.
The study how a substance (solute) can dissolve in another (solvent) which may be a gas, or
solid, or liquid has been an area of interest to the manufacturer to a researcher. By raising or
lowering the temperature, the solubility of a substance can changed. In other words,
solubility is a temperature dependent phenomenon. The term, solubility can be defined as
the concentration of dissolved solute in a solvent in equilibrium with undissolved solute at a
specific temperature and pressure . The solubility Data Commission of IUPAC has already
prepared and published more than 60 volumes of critically selected and evaluated solubility
data and more than 50 additional volumes in preparation of its Solubility Data Series. The
solubility of a substance can be expressed in various ways – parts of solute in parts of
solvent to percentage. Thus, different Pharmacopoeias have expressed differently. The
massive efforts have been made to generate the reliable solubility data. The gases may be
either polar or chemically react with water. If a gas ionizes in water and its ions can form
hydrates, it has a wide range of solubility such as HCl. In case of NH 3 , SO 2 , or CO 2 , this
is very different. The compounds such as NH 4 OH, H 2 SO 3 , and H 2 CO 3 formed due to
strong hydrogen bonding. NH 4 OH can also be written as NH 3 H 2 O. For high values CH
3
F, CH 3 Cl, and H 2 S hydrogen bonding or dipole-dipole interaction between the solute and
water is responsible.
As a rule, it can be said that like dissolves like. The word ‘like’ refers to the structure and
nature (polar) of the molecule. That is, the nonpolar solutes dissolve in nonpolar solvents
and polar solutes dissolve in polar solvents. For example, with all proportions of water at
room temperature methanol, ethanol, and 1-propanol are miscible because all these are polar
solutes with nonpolar tails. As the chain length increases the nonpolarity increases and
aqueous solubility decreases. For example, 7.9 g of 1-butanol dissolves in 100 g of water;
2.3 g of 1-pentanol dissolves in 100 g of water; and only 0.6 g of 1-hexanol dissolve in 100 g
of water.
The dissolution is a kinetic process. A solute may be poorly soluble in a solvent but may be
dissolved in another solvent in less time. On the other hand, a solute may be soluble in a
solvent but takes more time to be dissolved. There are many factors which can control the
solubility of a solute.
https://t.me/med1917
Solubility and dissolution are two different concepts, but both are interrelated. Dissolution or
solubilization is a thermodynamic process; the system will reach a lowest potential energy
(Gibbs free energy) after complete dissolution. The potential energy indicates the
thermodynamically most stable state. Solubility provides the information about the end point
of the phenomenon but not about the mechanism. Solubility tells us about the time required
for dissolving of certain amount of solute. The intermolecular interactions between the
solute and solvent molecules speak about the tendency of a solute to dissolve in a particular
solvent; this interaction finally leads to cohesive and adhesive forces between similar and
dissimilar molecules. The extent to which cohesive and adhesive forces exist between the
solute and solvent molecules correlates with the ability of a solvent to dissolve a particular
solute. The ability of a solvent depends on specific condition of temperature and atmospheric
pressure. Usually, changes in these two conditions vary the solubility. Once the full capacity
of a solvent to dissolve any further solute is reached (achieving supersaturated solution),
further addition of solute will simply result in settling at the bottom of the container
(aqueous solution). By changing the temperature, a saturated solution can be made
supersaturated. At unchanged temperature of the solvent, a concentration over the natural
capacity would be built up. The supersaturated solutions are not stable and easily precipitate
out the excess solute to reach the saturation point at a particular temperature.
The rate of dissolution can be expressed by Noyes-Whitney equation:
img
Where, img is the rate of dissolution, (kg/s)
m is the mass of dissolved material, (kg) t is the time, (s)
A is the surface area of the particle, (sq.m)
D is the diffusion coefficient, (m/s) partially related to viscosity of the solvent
d is the thickness of the concentration gradient, (m)
C s is the particle surface (saturation) concentration, (kg or moles/L), and
C b is the concentration in the bulk solvent/solution (kg or moles/L)
Therefore, solubility can be considered as an endpoint of dissolution capacity. The intrinsic
dissolution rate is the rate of dissolution of a pure solute, regulated by the surface area of the
solute which decreases with time. The Noyes-Whitney equation can be represented by the Fi
g 5.11.
img
Fig. 5.11 Factors of Noyes-Whitney for dissolution
https://t.me/med1917
•
With respect to dissolution process Noyes-Whitney equation provides much of practical
information such as:
Diffusion coefficient, D partly related to the viscosity of the solvent; the diffusion coefficient
decreases with increasing viscosity.
The rate of dissolution is inversely proportional to the viscosity of the solvent.
Dissolution rate, increases with reduction in particle size.
The rate of dissolution is directly proportional to the surface area of the particle. Thus,
micronization increases the rate of dissolution.
The rate of dissolution depends on the type of stirring or agitation. Thus, during dissolution
the agitation decreases the thickness of concentration gradient, d and increases the rate of
dissolution by removing the solute molecules from the surface of the solute particle.
Fig. 5.12 Schematic representation of dissolution process
The rate of dissolution depends on the pH of the solvent in case of ionizable and/or weak
electrolyte.
The pH of the solvent can change the saturation concentration or concentration at the
surface, C S . In other words, based on the nature of the solute and solvent, the change in pH
can increase or decrease the C S . Thus, by changing the pH, the concentration gradient can
be increased or decreased; thereby the rate of dissolution can be decreased or increased.
The factors that affect the total solubility
The factors that control the solubility of a solute depend on the nature and strength of the
solute-solvent attraction (interaction between solute and solvent molecules),
Polarity of the solute and solvent,
https://t.me/med1917
•
•
•
•
•
Temperature,
Thermodynamics of the dissolution,
Ionization of the solute and solvent, and
pH of the solvent
Intermolecular interaction
Opposite to the process of dissolution is the crystallization. The nature of attraction between
the solvent and solute molecules (adhesive force) is opposite to the nature of attraction
between the solvent molecules or solute molecules (cohesive force). These opposing facts
are mentioned below:
When the solvent molecules sufficiently interact with each other, the solute molecules
interact with the solvent molecules. The crystalline structure of the solute becomes weak and
then, separated by the solvent into individual ions, atoms, or molecules. Then the solute
molecule is engulfed by the solvent molecules. The process is represented in Fig 5.12.
Initially the solute molecule is removed from the crystal. The solute molecules rearrange in
such a way that a space is created within the group of solvent molecules. Then the isolated
solute molecule inserts into the space created by the solvent molecules. Since the solvent
molecules open to create a space for the solute molecule, the size and surface area of the
solute molecule is important. The larger solute molecule having smaller surface area keeps
contact with the solvent; while the solute molecule of smaller size will have larger area faces
difficulty for contacting with the solvent. Thus, the smaller particles will be dissolved faster
than the large sized particle. As a result, the solubility of solute decreases with increase in
size.
https://t.me/med1917
Fig. 5.13 Illustration of Young’s equation
Polarity of the solute and solvent
When the solvent molecules are polar, such as water, the polar solute molecules will be more
attracted than the nonpolar solute molecules. Although the nonpolar solutes will have some
attraction towards polar molecules through dipole–induced dipole actions, the magnitude of
these attractions would be much smaller. Therefore, polar solutes will generally be more
soluble in polar solvents.
Temperature
Solubility is affected by temperature. The effect of temperature on solubility varies with the
dissolution process– exothermic or endothermic. With the ambient environmental
conditions, heat would be absorbed in endothermic reactions (ΔH ˃ 0); while in exothermic
processes (ΔH < 0) the heat will be released. The relatively higher room temperature will not
favor the exothermic dissolution processes to proceed but will favor the endothermic
dissolution processes. Thus, at higher room temperature, the solubility of solutes with
endothermic process will be encouraged and the solubility of solutes with exothermic
process will be discouraged.
In simple language dissolution can be defined as the process of dispersing/dissociating a
solute in a solvent, forming a molecular dispersion, which is physically and chemically
homogeneous, called a solution . Out of different types of solutions, solid-in-liquid and
liquidin-liquid solutions are the most used and shall be discussed here. Broadly two types of
processes are involved in the preparation of solidin-liquid solutions– (1)In the solution state
the chemical entity of the solute remains same as is found in its original solid state. If the
solvent is removed from the solution, the solute is obtained unaltered, for example, solution
of sucrose in water. In such cases, the dissolution occurs without ionization of the solute.
Intermolecular interactions play the important role for dissolution to take place. (2) The
https://t.me/med1917
1.
2.
3.
original solute cannot be recovered either partially or completely. The solution contains a
solute whose structure remains different from that of the original solid form. Some change in
structure of solute takes place due to ionization or chemical interaction between solute and
solvent. Thus, when the solvent is removed from the solution, the solute obtained will have a
partial or complete change in structure. For example, when aspirin is dissolved in water,
aspirin hydrolyzes and form acetic acid and salicylic acid. On removal of water from the
solution, a mixture containing aspirin, acetic acid, and salicylic acid would be obtained
depending on the pH of water. In general, the process of dissolution involves three steps–
disintegration, deaggregation and then dissolution. The dissolution of fine particles again
involves three steps–
Wetting,
Immersion, and
Diffusion.
In wetting, there should be no interfacial tension between the particle and solvent is
inherently or reduced by adding suitable wetting agent. For easy dissolution, slow wetting of
the particles creates the problem. The air entrapped into the powder forms the air pockets
which slow down the initial ability of powder to meet the solvent and thus, increase the
interfacial tension. The ability of a solvent to wet a solute depends on the interfacial tension.
To calculate the surface tension values of solute and solvent, and to explain and predict the
wettability of solute, the Young’s equation can be used. The Young’s equation is expressed
as.
Where, γ
S/A
is the surface tension at solid-air boundary, γ
S/L
is the surface tension at solid-
liquid boundary,
L/A
is the surface tension at liquid-air boundary, and θ is the contact angle.
The Young’s equation is illustrated in Fig 5.11. When the value of θ is less than 90 o , the
solute is considered hydrophilic and when the value of θ is more than 90 o , the solute is
considered hydrophobic. Thus, when water is used as solvent, it can dissolve hydrophilic
solutes.
For dissolution initially spreading of solvent over the solid particle is required. The
spreading coefficient, S can be calculated as:
The solvent will completely spread over the surface of solid particle making the value of S
or (cos θ – 1) positive. On the other hand, when the value of S or (cos θ – 1) is found
negative, the spreading of solvent over the solid particle would be unfavorable or remains
incomplete.
https://t.me/med1917
Thermodynamics of the dissolution
The Gibb’s equation for free energy is ΔG = ΔH – TΔS; where ΔG is the energy for doing
work (change in Gibb’s free energy), ΔH is the change in enthalpy, ΔS is the change in
entropy, and T is the absolute temperature. When taken alone,the increase in enthalpy is
thermodynamically unfavorable; but increase in entropy is thermodynamically positive when
taken alone. When ΔG is negative, the system becomes overall thermodynamically
favorable. When the system is at isothermal condition,the Gibb’s equation can be used to
express the three steps of dissolution mentioned earlier. In step I, heat involved in breaking
of the solid lattice (freeing of solid particle) is represented thermodynamically as ΔH 1 ; ΔS
1
represents the increase in enthalpy but decreases entropy. In step II, the solvent molecules
open which is represented thermodynamically as ΔH 2 . In this step, the enthalpy increases to
ΔS 2 . The change in entropy depends on whether the solvent molecules are to be arranged
orderly. In step III, the solid particle inserts into the solvent. This is thermodynamically
represented as ΔH 3 . In this case, the enthalpy increases to ΔS 3 but entropy decreases.
Including three steps dissolution process, the overall free energy of the solution can be
calculated as:
For complete dissolution of a solute, the overall ΔG must be negative. Thus, ΣΔH must be
less than ΣΔS at a particular temperature, T.
Ionization of the solute and solvent, and pH of the solvent
According to Henderson-Hasselbalch equation,
Where,
[A – ] is the molar concentration of conjugate base (ionized form),
[HA] is the molar concentration of undissociated (unionized) weak acid,
The solubility of the polar solute will greatly depend on the pH of the solvent. Acidic drugs
will be less soluble in acid solutions but more in and basic solution because more of the drug
tends to remain in unionized form in acid pH and dissociate completely in basic pH. The
dependence of the solubility of an acidic drug (ionization of the acidic drug) in acidic
medium can be represented by (eqn. 5.7):
https://t.me/med1917
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Where, S is the solubility of the ionized drug, S o is the solubility of the unionized drug.
Similarly, the relation between the solubility of basic drug and pH of the medium can be
expressed as (eqn. 5.8);
Where, S′ is the solubility of the unionized drug, S o is the solubility of the ionized drug. The
zwitterions form of the drug has the lowest solubility, S o . At pH values below the
isoelectric point (pKa), the equation 5.8 and pH above the isoelectric point equation 5.7 is
used to calculate the solubility.
References
Jeffrey, L., Czeisier, Karl PP.; Diluents. In: James CB, James S, editors. Encyclopedia
of Pharmaceutical Technology. New York: Marcel Dekker; 1991.
Gohel, MC., Jogani, PD.; Functionality testing of a multifunctional directly
compressible adjuvant containing lactose, polyvinylpyrrolidone, and croscarmellose
sodium.; Pharm Technol.; 2002; 25:64–82.
Gohel, MC., Jogani, PD.; A review of co-processed directly compressible excipients.;
J Pharm Sci.; 2005; 8:76–93.
Guo, HX.; Compression behavior and enteric film coating properties of cellulose
esters [dissertation]. Finland: University of Helsinki; 2002.
Sun, C., Himmelspach, MW.; Reduced tabletability of roller compacted granules as a
result of granule size enlargement.; J Pharm Sci.; 2006, 95:200–6.
Leuenberger, H., Leu, R.; Formation of a tablet: a site and bond percolation
phenomenon.; J Pharm Sci.; 1992, 81:976–82.
Garekani, HA., Ford, JL., Rubinstein, MH., Rajabi-Siahboomi, AR.; Effect of
compression force, compression speed, and particle size on the compression properties
of paracetamol.; Drug Dev Ind Pharm.; 2001, 27:935–42.
Konkel, P., Mielck, JB.; Associations of parameters characterizing the time course of
the tableting process on a reciprocating and on a rotary tableting machine for highspeed production.; Eur J Pharm Biopharm.; 1998, 45:137–48.
Garekani, HA., Ford, JL., Rubinstein, MH., Rajabi-Siahboomi, AR.; Effect of
compression force, compression speed, and particle size on the compression properties
of paracetamol.; Drug Dev Ind. Pharm.; 2001, 27:935–42.
Sonnergaard, JM.; A critical evaluation of the Heckel equation.; Int J Pharm.;
1999,193:63–71.
https://t.me/med1917
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
Nokhodchi, A., Rubinstein, MH., Larhrib, H., Guyot, JC.; The effect of moisture
content on the energies involved in the compaction of ibuprofen.; Int J Pharm.; 1995,
120:13–20.
Schmidt, PC., Leitritz, M.; Compression force/time-profiles of microcrystalline
cellulose, dicalcium phosphate dihydrate and their binary mixtures-a critical
consideration of experimental parameters.; Eur J Pharm Biopharm.; 1997, 44:303–13.
Roberts, RJ, Rowe, RC.; The effect of punch velocity on the compaction of a variety
of materials.; J Pharm Pharmacol.; 1985, 37:377–84.
Akande, OF., Rubinstein, MH., Rowe, PH., Ford, JL.; Effect of compression speeds on
the compaction properties of a 1:1 paracetamol-microcrystalline cellulose mixture
prepared by single compression and by combinations of precompression and maincompression.; Int. J. Pharm.; 1997, 157:127–36.
Marshall K. “Compression and consolidation of powdered solids”, In: Lachman L,
Lieberman HA, Kanig JL, editors, “The Theory and Practice of Industrial Pharmacy",
3rd ed. Bombay, Varghese Publishing; 1987.
Booth SW, Newton JM. "Experimental investigation of adhesion between powders
and surfaces", J Pharm Pharmacol., 1987; 39: 679– 84.
Banker GS, Anderson NR., “Tablets”, In: Lachman L, Liberman HA, Kanig JL,
editors "The Theory and Practice of Industrial Pharmacy", 3rd ed., Bombay, Varghese
Publishing; 1976.
Adam A, Schrimpl L, Schmidt PC. Factors influencing capping and cracking of
mefenamic acid tablets. Drug Dev Ind Pharm. 2000;26:489–97.
Jonat S, Hasenzahl S, Gray A, Schmidt PC. Mechanism of glidants: investigation of
the effect of different colloidal silicon dioxide types on powder flow by atomic force
and scanning electron microscopy. J Pharm Sci. 2004;93:2635–44.
Jarosz PJ, Parrott EL. Effect of lubricants on tensile strengths of tablets. Drug Dev Ind
Pharm. 1984;10:259–73.
Davies P. Oral solid dosage forms. In: Gibson M, editor. Pharmaceutical
Preformulation and Formulation. Colorado: Interpharm; 2001.
Marshall K. Compression and consolidation of powdered solids. In: Lachman L,
Lieberman HA, Kanig JL, editors. The Theory and Practice of Industrial Pharmacy.
3rd ed. Bombay: Varghese Publishing; 1987.
Alpar O, Hersey JA, Shotton E. The compression properties of lactose. J Pharm
Pharmacol. 1970;22 (Suppl.):1S–7S.
Joiris E, Di Martino P, Berneron C, Guyot-Hermann AM, Guyot JC. Compression
behavior of orthorhombic paracetamol. Pharm Res. 1998;15:1122–30.
https://t.me/med1917
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
Rippie EG, Danielson DW. Viscoelastic stress/strain behavior of pharmaceutical
tablets: analysis during unloading and postcompression periods. J Pharm Sci.
1981;70:476–82.
Rees JE, Rue PJ. Time-dependent deformation of some direct compression excipients.
J Pharm Pharmacol. 1978;30:601–7.
Abberger T, Henck JO. Granule formation mechanisms in fluidbed melt granulation
and their effects on tablet properties. Pharmazie. 2000;55:521–6.
Jarosz PJ, Parrott EL. Effect of lubricants on tensile strengths of tablets. Drug Dev Ind
Pharm. 1984;10:259–73.
Ebba F, Piccerelle P, Prinderre P, Opota D, Joachim J. Stress relaxation studies of
granules as a function of different lubricants. Eur J Pharm Biopharm. 2001;52:211–20.
Casahoursat L, Lemagen G, Larrouture D. The use of stress relaxation trials to
characterize tablet capping. Drug Dev Ind Pharm. 1988;14:2179–99.
Rao KP, Chawla G, Kaushal AM, Bansal AK. Impact of solidstate properties on
lubrication efficacy of magnesium stearate. Pharm Dev Technol. 2005;10:423–37.
Alderborn G, Ahlneck C. Moisture adsorption and tabletting. III. Effect on tablet
strength-post compaction storage time profiles. Int J Pharm. 1991;73:249–58.
Carr RL. Evaluating flow properties of solids. Chem Eng. 1965;72:163–8.
Satoru W, Tomoko Y, Yoshifumi O, Masamitsu T. Development of a novel
compression tester and rheo-mechanical properties of wet-mass powder. II effect of
moisture content on the rheo-mechanical properties. Chem Pharm Bull. 2003;51:751–
3.
Nokhodchi A, Rubinstein MH, Larhrib H, Guyot JC. The effect of moisture content on
the energies involved in the compaction of ibuprofen. Int J Pharm. 1995;120:13–20.
Li LC, Peck GE. The effect of moisture content on the compression properties of
maltodextrins. J Pharm Pharmacol. 1990;42:272–5.
Sun C. True density of microcrystalline cellulose. J Pharm Sci. 2005;94:2132–4.
Rees JE, Hersey JA. The strength of compacts containing moisture. Pharm Acta
Helve. 1972;47:235–43.
Schepky G. Preformulation: The role of moisture in solid dosage forms. Drug Dev Ind
Pharm. 1989;15:1715–41.
Dawoodbahai C, Rhodes CT. The effect of moisture on powder flow and on
compaction and physical stability of tablets. Drug Dev Ind Pharm. 1989;15:1577–600.
Doelker E, Massuelle D. Benefits of die-wall instrumentation for research and
development in tabletting. Eur J Pharm Biopharm. 2004;58:427–44.
https://t.me/med1917
Соседние файлы в папке Библиотека им академика М.И. Перельмана