Dissolution is the one of the most important basic and forming operation in pharmaceutical technology.
In a pharmaceutical technology, dissolution means the operation, during which a materials in solid, liquid or gas state of matter is dispersed in a solvent in molecular level. Thus to dissolve can regarded as a special form of to disperse. If the molecular size of dissolved material is lower, than 1nm, then molecular, if is higher than 500 nm, but not more than 1µm, then colloidal is the dissolution.
Absorption from preparation can develop directly from solution-type preparations (e.g. solutions, injections) or indirectly, when active ingredients have to liberate and dissolve previously to be ready to be absorbed.
In biopharmacy point of view, process of dissolution is one of the important criteria of absorption:
1) previously dissolved medicine before administration (e.g. effervescent tablet), and
2) dissolution process occurring in living organization, which can be:
2.1) dissolution of active substance after taking or applying (e.g.
medical powders),
2.2) fast dissolving (e.g. sublingual preparation),
2.3) dissolution or liberation can occur from preparation,
2.3.1) uncontrolled way (e.g. suppository, conventional tablet) and 2.3.2) controlled way
in space,
in time,
in space and time.
Dissolution of excipients (e.g. coating, matrix) frequently and significantly affects dissolution process and starts parallel with liberation of APIs.
From solutions and nano systems (e.g. dendrimers, inclusion complexes) absorption is faster; because molecules are ready to be absorbed in the view of molecular dispersion degree, and there is no need previous disintegration processes (as a criteria of dissolution process). Absorption of preparation regarded to such molecular systems is influenced and determined after per oral administration by quantity of API molecules in non-ionic state. The ionic and non-ionic state depends on pH value of local gastrointestinal tractand pK, based on Henderson- Hasselbach equation.
For perfect absorption of a particular molecule ttransit time is only available. If dissolution (in the case of preparation, liberation) is just performed partially, then perfect, total absorption cannot be expected and biological availability/ bioavailability (BA) of the preparation will be low (BA<1,or BA<<1). Low BA can occur due to the fact that certain amount of administered API passes intestine section with absorption capability. These points of view have to be considered at design of biopharmacy parameters, control of location and speed of dissolution and at determination of required dosage.
Fig. 11.1.
The effect of solubility, dissolution speed and transit time on bioavailability and applied dose
Solutions can be administered in the following ways:
1) oral (e.g. mouthwashes, gum preparations),
2) peroral (e.g. solutions, elixirs, mixtures, syrups, decoctions, infusions), 3) dermal and transdermal (e.g. solutions, decoctions, infusions, ointments,
creams),
4) ocular (e.g. eye drops, eye washes),
5) vaginal (e.g. vaginal solutions and washes), 6) rectal (e.g. enema),
7) parenteral (e.g. injections, infusions).
The solutions, mixtures, or solution –type solid dispersions or mixture of gases are multicomponent (number of components, nk ≥2), monophasic (number of phases, nf =1) homogeneous materials structures.
Pharmaceutical solutions are homogeneous liquid dispersion of a solute (solid, liquid or gas) dissolved in a suitable vehicle (water, alcohol or any other solvent mixture).
General operation steps of dissolution shown in Figure 2.
Chapter 11: Dissolution
Fig. 11.2.
General operation steps of dissolution
Most important characteristics that need to be considered when compounding solutions are solubility and stability.
The majority of processes occurring in nature take place in solution. In laboratory -, and industrial sizes, implementation of chemical reactions, manufacture operations is generally in liquid phase, mostly in solutions.
Solutions, drops, eye drops are independent dosage forms, at preparation which solubility properties of materials have to be known. Operation of dissolution plays a significant role in pharmaceutical monitoring, control.
The process of dissolution can be performed in physical and in chemical way.
The point of physical dissolution is that during process, the two materials do not change the structure of each other (e.g. solution of sodium chloride or sucrose). The process is reversible, namely dissolved material can be extracted by evaporation of solution.
Chemical dissolution is when two material interact with each other in a chemical interaction, which result in a new structure material (e.g. Fe +2HCl = FeCl2 + H2). The process is irreversible.
At physical dissolution, two or more phasic system may gradually turn into one phase and homogeneous status may be created. Before and after the operation, the number of components will not be changed, but number of phases can increase to the original value above the saturation concentration (due to separation of crystals).
In the case of liquids, which are miscible unlimitedly in each other, the dissolution is termed mixing. Before and after the operation, number of phases and components does not change for example the mixture of water-ethanol, or benzene and toluene.
Other type of liquids can be mixed until a limit in each other, such as water and phenol, or water and ether.
Dissolution is the result of interaction between the molecules of solvent and dissolving material. In both material, one part of the interparticle bonding (secondary) are broken and new bonding are created among solvent and dissolved material.
In dissolution process, solvation is created between molecules of dissolved material and solvent, in addition to the fact that in case of water solvent, is termed hydration. Solvation is the connection or interaction creation between the molecules of dissolved substance and solvent. The point of process is the creation of a solvation shell or a hydration shell around a molecule or an ion.
At solvation, different type intermolecular interactions can develop: hydrogen bonding, ion-dipole, dipole-dipole or van der Waals forces. Hydrogen bonding, ion-dipole, dipole-dipole forces occur only in polar, hydrophilic solvents. Ion-ion interactions present in ionic solvents. In case of lack of these, van der Waals forces present. The hydrate shells around ions (because the most frequent used solvent is water)” shroud” the opposite charged ions, hence ions cannot unite and create salt. The solutions of ions, which are able to move freely, are termed electrolyte solutions, while it conducts electricity.
At dissolution of salt type molecules in water, the molar free energy of solution can be calculated by this formula:
lattice anion
cation
solution G G G
G =∆ +∆ −∆
∆ (1.)
cation
∆G molar hydration free energy of the cation,
anion
∆G molar hydration free energy of the anion,
lattice
∆G free energy of crystal-lattice.
Fig. 11.3.
The process of hydration based on ion-dipole forces
In solvation process, the molecules of dissolving material have to escape from crystal-lattice in order to be stabilized in the solvent by the interaction with molecules of solvent.
In order to escape the units of crystal lattice, lattice energy (Elattice) has to be exerted to overcome the force between the molecules of dissolving material.
Between the molecules of solvent are also cohesive forces, but their energy level is much lower than lattice energy.
Water as a solvent has a strong dipole force, and is built up by molecules connected with hydrogen bridges. Primarily water is able to create and maintain
ion-Chapter 11: Dissolution
Water is able to separate opposite charged particles, and to stabilize ions and dipole-type molecules.
At dissolution, between particles of solvent and dissolved material, new coherent force is created, which is associated with energy release. This energy is solvation energy (Esolv), what is termed hydration energy (Ehydr) in the case of water.
Heat of solution is the heat, which is released or absorbed, if quantity of one mole material is dissolved in large excess of solvent. Heat of solution is characterized in dissolution process by algebraic sum of used lattice and released hydration energy:
dissolv
∆H =Elattice + Ehydr (2.)
The sign of heat of solution can be positive, when the process is endothermic, and if it is negative, then it is an exothermic process. (Lattice, hydration energy and heat of solution is calculated per mole.)
In case of exothermic process, the system lose energy (during rearrangement of bonds, its total energy decrease), more energy is released during the dissolution process, than can be used. This energy rises the temperature of environment with the temperature of solution. At dissolution of crystalized material, the energy level of molecules goes from a higher energy lattice level to a lower, hydrated energy level, therefore energy is released:
Elattice<Ehydr (3.)
Thus heat of solution is a negative value, because the material releases heat. For example heat of solution is at dissolution of NaOH: –42,2 kJ/mole, in the case of Na2SO4: -1,9 kJ/mol.
In the case of endothermic dissolution process, the situation is the opposite, because the internal temperature increase, during the dissolution process less energy is released, than is used:
Elattice>Ehydr (4.)
Thus heat of solution is a positive value, because the material receives heat. For example heat of solution is at dissolution of KNO3: +35,1 kJ/mole, in the case of NaCl:+4kJ kJ/mol.
The molecules of solvent are targeted to surround and separate dissolved molecules.
Dissolution takes place in at least three steps:
1) solvent and dissolving material has to get contact with each other,
2) chemical or physical processes of dissolution take place on the boundary surface with creating the most concentrated solution layer,
3) dissolved material has to move toward to the inside of solution, in order to assist continuation of dissolution process.
In the view of dissolution process, the structure of dissolving material and stability of the developing new structure are fundamentally important.
At dissolution of crystallized material, the entropy generally increases, while order of the system decrease when a less organized solution is created from an ordered crystalline status.
Fig. 11.4.
Dissolution mechanism of crystalline material
The pharmaceutical definition of solubility is the mass proportion of dissolved material and solvent in a saturated solution. It shows the dissolution, that a mass unit of dissolving material can dissolve in how many mass unit of solvent. In other words, the concentration of dissolved material in certain saturated solution in particular temperature and pressure. The solubility plays a very important role in design, implementation of several technological processes.
According to saturation concentration the following groups can be distinguished:
1) unsaturated solution, which is able to dissolve more additional material in it,
2) saturated solution, which contains the maximum of the particular material,
3) oversaturated solution, which contains more quantity of material than the saturated solution.
In the case of unsaturated solution (c<ct), concentration can be increased until the saturation concentration. At saturation, dynamic balance develops among dissolving and separating material. Oversaturation (c>ct) is only a temporary, instable status containing more material than saturated solution.
Table 11-I.
Most frequent applied solvent in pharmaceutical practice
Solvent Specifications
Freezing point Boiling point Hydrophilic Hydrophobic
acetone -94.6 56.5 +
acetonitrile -40 82 +
Chapter 11: Dissolution
Solvent Specifications
Freezing point Boiling point Hydrophilic Hydrophobic
aniline -6.2 184.4 Limited
benzene 5.5 80.1 +
cyclohexane 6.5 83.3 +
diethyl ether -116.3 34.6 +
diethyl amine -38.9 55.5 +
dimethyl sulfoxide 19 189 +
ethanol -112 78.4 +
ethyl acetate -82.4 77 Limited
Ethylene glycol -11.5 197.5 +
phenol 42 181.8 Limited
formaldehyde -92 -21 +
glycerol 17.9 290 +
isopropyl ether -60 67.5 +
isopropanol -90 82.4 +
isopropyl acetate -73.4 89.4 Limited
Isopropyl myristate ~5 140,2
(266Pa) +
chloroform -63.5 61.2 +
methanol 97 64.7 +
methylene chloride -96.7 40 Limited
n-amyl acetate -70.8 148.4 Limited
n-butyl acetate -76.3 125 +
n-butyl alcohol -79.9 117 +
n-heptane -90.6 98.4 +
n-hexane -94 69 +
n-propanol -127 97.8 +
octanol (n) -16 194 +
pyridine -42 115 +
polyethylene glycol 600 15-25
(freezing) +
propylene glycol - 188 +
toluene -95 110.8 +
triethyl amine -114.8 89.4 +
water 0 100 +
Legend: ++ well miscible, + partially miscible, - inmiscibl
The expression, distilled water means that the water purified by distillation.
According to pharmacopoeias, several waters used in pharmaceuticals can be distinguished.
1) Purified water (Aqua purificata) is a water for preparation of those compounded medicines, which has not to be sterile and pyrogen-free (e.g. solutions, emulsions, suspensions, drops excluding eye drops),
excepted justified and officially approved cases. Two types of purified water are distinguished, purified water in bulk, and in containers.
1.1) Purified water in bulk is prepared by distillation, by ion exchange, by reverse osmosis or by any other suitable method from water that complies with the regulations on water intended for human consumption laid down by the competent authority. According to the criteria of pharmacopoeia, water in bulk has to be:
a.) clear and colorless liquid,
b.)met with criteria of microbial monitoring
c.)appropriate in pH, as well as its specific conductivity
d.) less nitrate, aluminum or heavy metal in it, than the allowed limit
e.)at most the concentration of bacterial endotoxin in it, than the allowed 0.25 IU/ml.
The storage and filling conditions has to be created to exclude proliferation of microorganisms and any other contamination.
1.2) Purified water in container, that has been filled and stored in conditions designed to assure the required microbiological quality.
It is free from any added substances.
2) Water for injections (Aqua ad iniectabilia) can be in bulk and sterilized water for injection. Water for the preparation of medicines for parenteral application, when water is used as a vehicle (water for injection in bulk), and dissolving or diluting substances or preparation for parenteral administration (sterilized water for injection).
2.1) Water for injections in bulk is obtained from water that complies with the regulations on water intended for human consumption laid down by the competent authority or which the parts in contact with water are of neutral glass, quartz or suitable metal and which is fitted with an effective device to prevent the entertainment of droplets. The correct maintenance if the apparatus is essential. The first portion of the distillate obtained when the apparatus begins to function is discarded and the distillate is collected. The assurance of water quality is controlled by validated methods, by in process conductivity measurements, and by gradual microbiological monitoring. Storage and distributing water for injection in bulk has to be managed to exclude growth of microorganisms and any other contamination. Based on the criteria of the Pharmacopoeia has to be:
a) clear and colorless liquid,
b) appropriate in pH, as well as its specific conductivity,
c) less nitrate, aluminum or heavy metal in it, than the allowed limit
d) at most the concentration of bacterial endotoxin in it, than the allowed 0.25 IU/ml.
2.2) Water for injection in bulk that has been distributed into suitable
Chapter 11: Dissolution
has to be met with the criteria of sterilization. Sterilized water for injections is used to dissolve or dilute substances in parenteral preparation (e.g. in situ preparation of injection from vials). Based on the criteria of Pharmacopoeia, sterilized water for injection has to be:
a) clear and colorless liquid,
b) appropriate in pH, as well as its specific conductivity,
c) less oxidizable substances, chloride, nitrate, sulphate, aluminum, calcium, magnesium, and heavy metal in it, than the allowed limit
d) at most 4mg (0,004%) after evaporated (evaporation leftover) e) at most the concentration of bacterial endotoxin in it, than the
allowed 0.25 IU/ml.
3) Water, high purified (Aqua valde purificata) intended for use in preparation if medicinal product where water of high biological quality is needed, except where Water for injection is required.
4) Water for dilution concentrated hemodialysis solutions is obtained from potable water by distillation, by reverse osmosis, by ion exchange or by any suitable method. The conditions of preparation, transfer and storage are designed to minimize the risk of chemical and microbial contamination. When water obtained by one of the methods described above is not available, potable water may be used for home dialysis.
Because the chemical composition of potable water varies considerably from one local to another, consideration must be given to its chemical composition to enable adjustment. Quality of water for dilution concentrated hemodialysis has to be controlled gradually including acidity, alkalinity, oxidizable substances, content of total available chlorine, chloride, fluorides, nitrates, sulphates, aluminum, ammonium, calcium, magnesium, mercury, potassium, sodium, zinc, heavy metals, and also microbial contamination as well as bacterial endotoxins.
11.1 Solubility
Solubility, the property of substances, means the amount of a substance that dissolves in a unit volume of a solvent to form a saturated solution under specified conditions of temperature and pressure.
The solubility of a substance fundamentally depends on the used solvent as well as on temperature and pressure. Solubility values in pharmacopoeia pertain to 15–25 °C temperature intervals.
Table 11-II.
Specific intervals of solubility
Descriptive term Approximate volume of solvent in millilitres per gram of solute
very soluble <1
freely soluble 1-10
sparingly soluble 10-100
Descriptive term Approximate volume of solvent in millilitres per gram of solute
slightly soluble 100-1000
very slightly soluble 1000-10000
practically insoluble >10000
The term “partly soluble” is used to describe a mixture where only some of the components dissolve. The term „miscible” is used to describe a liquid that is miscible in all proportion with the started solvent.
Solubility depends on several factors, such as solvent, dissolving material, temperature and in the case of solubility of gases it depends on partial pressure of the component. Therefore solubility is generally given in 20°C.
Solubility can be characterized in several ways:
a) solubility equilibrium or namely thermodynamic solubility, which means the concentration of a saturated solution in which the dissolved material is in redundancy.
b) intrinsic solubility is the balance solubility of free acid or alkali form of ion-type substances in a certain pH, in which the substance presents in totally unionized form.
c) kinetic solubility is the concentration value, in which substance is firstly separated from solution in insoluble form.
d) apparent solubility is determined in solutions or puffers in several pH, therefore apparent solubility depends on pH and ionic strength of the medium.
In order to determine thermodynamic solubility, the substance has to be mixed in redundancy to particular volume of aqueous medium, in particular temperature until a particular time (frequently until 24 or 48 hours), then concentration of saturated solution can be determined with a suitable analytical methods by extracting the filtrate (by filtering/ centrifugation).
Kinetic solubility can be ascertained that the solid material is dissolved in organic solvent in a low concentration, and then a small part of this solution is mixed with aqueous puffers. When the material firstly precipitates, then it has to be separated from the solution and concentration is determined.
Jain and Yalkowsky have introduced the General Solubility Equation, GSE, which gives the correlation of effective solubility:
P log ) 25 T ( 01 , 0 5 , 0 S
log 0 = − m− − (5.)
S0 effective solubility, Tm melting point,
P octanol/ water partition coefficient.
Based on Henry-Dalton rule, solubility of gas without reacting with liquid depends on pressure:
Chapter 11: Dissolution
The higher is the concentration of dissolved material, bigger is the difference from this rule. The reason of behavior differing from ideal is due to interactions of molecules and ions in so called true solutions.
In the case of solutions, solubility depends principally rather on temperature and less on pressure. Temperature dependence of solubility of different materials is various.
By rising temperature for example, solubility of saccharose and KNO3 increase, but solubility of Na2SO4 decrease. In the case of NaCl, NaBr, KCl, solubility is not changed by temperature.
Fig. 11.5.
Change in solubility of several materials in the function of temperature
Temperature dependence of solubility is described in Clausius-Clapeyron correlation:
1 2
1 2 diss T
T
T RT 3 , 2
) T T ( H S
lg S
2
1 −
= ∆
(7.)
T1
S , ST2 solubility in certain temperatures (T2,T1)
If heat of solution has negative sign (exothermic dissolution), then solubility decrease, but if it is positive (endothermic dissolution), then solubility increases by rising temperature.
Most frequently the materials which should be dissolved belong to weak electrolyte type substances. In this case, pH of the medium is also a significant parameter in the view of solubility. According to dissociation equilibrium, the material presents in dissociated and not dissociated form at the same time. The sum of two solubility is (Ss):
in the case of weak acids:
pH d 0 0
t S S K 10
S = + (8.)
in the case of weak alkali:
pH d 0 0
t 10
K S S
S = + − (9.)
11.2 Increase of solubility
Increase of solubility can developed with caution in every case. Physical chemical thereby biopharmacy properties of active substance can be modified by changing of molecular-chemical structure, increase or decrease of polar nature. These methods can be only applied, if original therapeutic effect of active ingredient is kept.
Polymorphism, hydration, solvation, and amorphous forms of solid crystals influence the speed of dissolution. One possibility to modify manufacturability, solubility and speed of dissolution is to turn the substance to amorphous form. This method is just considered, when the substance prones to form into polymorph form or the workability of certain crystal form is difficult. In amorphous state the chemical stability decreases due to absence of crystal lattice. The crystal lattice has a long term orientation, while material with amorphous structure has got only short-time orientation.
In practice, this means that amorphous material has higher solubility. It is very important about amorphous materials that higher is the probability for recrystallization and to turn into another crystal form with lower solubility due to the instable status of amorphous structure. In order to maintain the amorphous structure, hindering of transformation of structure is needed in more stable state. The solution can be the dispersion of amorphous substance in a solid dispersion, which slows down the recrystallization process by hindering the internal movements.
One of the most common solutions for increase of solubility is salification or salt formation in the case of weak acid and alkali substances.
Choice of suitable salt form depends on:
solubility,
hygroscopic character,
stability and
toxicological properties.
With this solution, ephedrine can be formed to ephedrine hydrochloride and phenobarbital into phenobarbital sodium