Marketing Visionario Hipótesis especifica 3

Each drug substance has intrinsic chemical and physical characteristics that must be considered before the development of its pharmaceutical formulation. Among these characteristics are the particle size, surface area, the drug’s solubility, pH, parti-tion coefficient, dissoluparti-tion rate, physical form, and stability. All these factors are TABLE 2.1

List of Pharmaceutical Ingredients

Ingredients Definition Examples

Antifungal preservatives

Used in liquid and semi-solid

formulations to prevent growth of fungi

Benzoic acid, butylparaben, ethylparaben, sodium benzoate, sodium propionate Antimicrobial

preservatives

Used in liquid and semi-solid formulations to prevent growth of microorganisms

Benzalkonium chloride, benzyl alcohol, cetylpyridinium chloride, phenyl ethyl alcohol

Antioxidant Used to prevent oxidation Ascorbic acid, ascorbyl palmitate, sodium ascorbate, sodium bisulfite, sodium metabisulfite

Emulsifying agent

Used to promote and maintain dispersion of finely divided particles of a liquid in a vehicle in which it is immiscible

Acacia, cetyl alcohol, glyceryl monostearate, sorbitan monostearate Surfactant Used to reduce surface or interfacial

tension

Polysorbate 80, sodium lauryl sulfate, sorbitan monopalmitate

Plasticizer Used to enhance coat spread over tablets, beads, and granules

Glycerin, diethyl palmitate Suspending

agent

Used to reduce sedimentation rate of drug particles dispersed throughout a vehicle in they are not soluble

Carbopol, hydroxymethylcellulose, hydroxypropyl cellulose, methylcellulose, tragacanth

discussed in the following, except the particle size and dissolution rate, which will be discussed in the next chapter.

2.3.1  m^olecular S^ize anD v^olume

Molecular size and volume have important implications for drug absorption. Tight junctions can block the passage of even relatively small molecules, whereas gap junc-tions are looser and molecules up to 1200 Da can pass freely between cells. However, larger molecules cannot pass through gap junctions. Drug diffusion in simple liquid is expressed by the Stokes–Einstein equation:

D RT

= r 6πη where

D is the diffusion of drugs

R is the gas constant = 8.313 JK⁻¹ mol⁻¹ T is the temperature (K)

η is the solvent viscosity

r is the solvated radius of diffusing solute

Since volume (V) = (4/3) πr³, the aforementioned equation suggests that drug dif-fusivity is inversely proportional to the molecular volume. Molecular volume is dependent on molecular weight, conformation and heteroatom content. Molecules with a compact conformation will have a lower molecular volume and thus a higher diffusivity. As shown in Figure 2.1, the diffusion and permeability of the endothelial monolayer to molecules decreased with increasing molecular weight.

A drug must diffuse through a variety of biological membranes after administra-tion into the body. In addiadministra-tion, drugs in many controlled release systems must dif-fuse through a rate-controlling membrane or matrix. The ability of a drug to difdif-fuse through membranes is a function of its molecular size and volume. For drugs with

1.1

0.7 0.5 0.9

0.1 0.3

–0.1

Molecular weight (Da)

(A) (B)

Diffusion (D ×10–5 cm2/s)

10² 10³ 10⁴ 10⁵ 10⁶

0.9

0.5 0.7

0.1 0.3

–3Permeability (cm/s ×10)–0.1

Molecular weight (Da)

10² 10³ 10⁴ 10⁵ 10⁶

FIGURE 2.1 Diffusion (A) and permeability (B) of different molecular weight compounds across an endothelial monolayer at 37°C.

18 Pharmaceutical Dosage Forms and Drug Delivery a molecular weight greater than 500, their diffusion in many polymeric matrices is very small. Lipinski devised the so-called “Rule of 5” which refers to drug-like properties of molecules. It states that poor oral absorption is more likely when the drug molecule has

• More than five hydrogen-bond donors (–OH groups or –NH groups)

• A molecular weight >800

• A log P > 5

• More than 10H-bond acceptors

However, this rule is not applicable to the compounds that are substrates for transporters.

2.3.2  D^rug S^{olubility anD P}h

Pharmacological activity is dependent on solubilization of a drug substance in physi-ological fluids. Therefore, a drug substance must possess some aqueous solubility for systemic absorption and therapeutic response. Enhanced aqueous solubility may be achieved by forming salts or esters; by chemical complexation; or by reducing the drug’s particle size (i.e., micronization); or creating an amorphous solid. One of the most important factors in the formulation process is pH, as it affects solubility and stability of weakly acidic or basic compounds. Changes in pH can lead to ionization or salt formation. Adjustment in pH is often used to increase the solubility of ioniz-able drugs because the ionized molecular species has higher water solubility than its neutral species. According to Equations 2.1 and 2.2, the total solubility, S_T, is the function of intrinsic solubility, S₀, and the difference between the molecule’s pK_a and the solution pH. The intrinsic solubility is the solubility of the neutral species.

Weak acids can be solubilized at pHs below their acidic pK_a, while weak bases can be solubilized at pHs above their basic pK_a. For every pH unit away from the pK_a, the weak acid/base solubility increases 10-fold. Thus, solubility can be achieved as long as the formulation pH is at least three units away from the pK_a. Adjusting solution pH is the simplest and most common method to increase water solubility in inject-able products:

For a weak acidST=S0(1 1+ 0pH p^{− Ka}) (2.1) For a weak acidST=S0(1 1+ 0p^Ka−pH) (2.2) Unlike a weak acid or weak base, the solubility of a strong acid or base is less affected by pH. The drugs without ionizable groups are often solubilized by the combination of an aqueous solution and water soluble organic solvent/surfactant. Frequently a solute is more soluble in a mixture of solvents than in one solvent alone. This phe-nomenon is known as cosolvency, and the solvents, that is combination, increase the solubility of the solute are called cosolvents. The addition of a cosolvent can increase the solubility of hydrophobic molecules by reducing the dielectric constant, which is

a measure of the influence by a medium on the energy needed to separate two oppo-sitely charged bodies. Some of cosolvents commonly being used in pharmaceutical formulations include ethyl alcohol, glycerin, sorbitol, propylene glycol, and poly-ethylene glycol. Polypoly-ethylene glycol (PEG) 300 or 400, propylene glycol, glycerin, dimethylacetamide (DMA), N-methyl 2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), cremophore, and polysorbate 80 are often used for solubilization of drugs that have no ionizable groups. As shown in Figure 2.2, the solubility of phenobarbital is, for example, significantly increased in a mixture of water, alcohol, and glycerin compared to one of these solvents alone. However, the use of cosolvents often leads to the precipitation of the drug upon dilution during the administration of the drug solution into the body, resulting in pain or tissue damage.

Excipients that solubilize a molecule via specific interactions, such as complex-ation with a drug molecule in a noncovalent manner lower the chemical potential of the molecules in solution. These noncovalent solubility-enhancing interactions are the basis of the phenomenon that like dissolves like and include van der Waals forces, hydrogen bonding, dipole–dipole, ion–dipole interactions, and in certain cases favorable electromagnetic interactions. Solutes dissolve better in solvents of similar polarity. Therefore, to dissolve a highly polar or ionic compound, one should use a solvent that is highly polar or has a high dielectric constant. On the contrary, to dissolve a drug that is nonpolar, one should use a solvent that is relatively nonpolar or has a low dielectric constant.

Drug solubility can also be enhanced by altering its structure; this is one basis for the use of prodrugs. A prodrug is a drug that is therapeutically inactive when admin-istered, but becomes activated in the body by chemical or enzymatic processing. The addition of polar groups, such as carboxylic acids, ketones, and amines can increase

90%

80%

30 20 10 75 43 2

0 20 40 60

Solubility of phenobarbital in water

80 Alcohol in solvent (% by volume)100 1

Phenobarbital (%W/V) 0.50.7

0.40.3 0.2 0.1

70%60%50% 40% 30% 20%10%

Glycerin0%

FIGURE 2.2 Effect of cosolvents on the solubility of phenobarbital in a mixture of water, alcohol, and glycerin at 25°C. (Reproduced from Krause, G.M. and Gross, J.M., J. Am.

Pharm. Assoc. Ed. 40, 137, 1951. With permission.)

20 Pharmaceutical Dosage Forms and Drug Delivery

aqueous solubility by increasing the hydrogen bonding and the dipole–dipole inter-action between the drug molecule and the water molecules. Table 2.2 lists different substituents, which will have significant influence on the water solubility of drugs.

Substituents can be classified as either hydrophobic or hydrophilic, depending on their polarity. The position of the substituents on the molecule can also influence its effect.

2.3.3  liPoPhilicity ^anD P^artition c^oefficient

Partitioning is the ability of a compound to distribute in two immiscible liquids.

When a weak acid or base drug is added to two immiscible liquids, some drug goes to the nonpolar phase and some drug goes to the aqueous layer. Because like dis-solves like, the nonpolar species migrate (partitions) to the nonpolar layer and the polar species migrate to the polar aqueous layer.

To produce a pharmacologic response, a drug molecule must first cross a biologic membrane, which acts as a lipophilic barrier to many drugs. Since passive diffusion is the predominant mechanism by which many drugs are transported, the lipophilic nature of the molecules is important. A drug’s partition coefficient is a measure of its distribution in a lipophilic–hydrophilic phase system and indicates its ability to penetrate biologic multiphase systems. The octanol–water partition coefficient is commonly used in formulation development and defined as

P =(Concentration of drug in octanol or nonpolar phase) (Concc. of drug in water or polar phase) TABLE 2.2

Water Solubility of Different Substituent Groups

Hydrophobic substituent groups –CH₃

–CH²– –Cl, –Br –N(CH³)2

–SCH₃ –OCH₂CH₃

Hydrophilic substituent groups OCH₃

–NO₂ –CHO –COOH –COO–

–NH₂ –NH₃⁺ –OH

For an ionizable drug, the following equation is applicable:

P =(Concentration of drug in octanol or nonpolar phase) [(1 − αα)(Conc. of drug in water or polar phase)]

In this equation, α is equal to the degree of ionization. The concentration in aque-ous phase is estimated by an analytical assay, and concentration in octanol or other organic phases is deduced by subtracting the aqueous amount from the total amount placed in the solvents. Partition coefficient can be used for drug extraction from plants or biologic fluids, drug absorption from dosage forms, and recovering antibi-otics from fermentation broth.

The logarithm of partition coefficient (P) is known as log P. Log P is a measure of lipophilicity, and is used widely since many pharmaceutical and biological events depend on lipophilic characteristics. Often, the log P of a compound is quoted.

Table 2.3 lists the log P values of some representative compounds. For a given drug, If log P = 0, equal drug distribution in both phases.

If log P > 0, the drug is lipid soluble.

If log P < 0, the drug is water soluble.

In general, the higher the log P, the higher is the affinity for lipid membranes and thus the more rapidly the drug passes through the membrane via passive diffusion.

However, there is a parabolic relationship between log P and drug activity when per-centage of drug absorption is plotted against log P values (Figure 2.3). The parabolic nature of bioactivity and log P values is due to the fact that drugs with high log P values, protein binding, low solubility, and binding to extraneous sites causes them to have a lower bioactivity. Decrease in activity is due to the limitation in solubility beyond certain log P value. If a drug is too lipophilic, it will remain in the lipidic membrane and not partition out again into the underlying aqueous environment. On the other hand, very polar compounds with very high log P values are not sufficiently lipophilic to be able to pass through lipid membrane barriers.

2.3.4  PolymorPhiSm

The capacity of a substance to exist in more than one solid state forms is a property known as polymorphism, and the different crystalline forms are called polymorphs.

If the change from one polymorph to another is reversible, the process is enantio-tropic. However, if the transition from a metastable to a stable polymorph is uni-directional, the system is monotropic. Polymorphic forms may exhibit detectable differences in some or all of the following properties: melting point, dissolution rate, solubility, and stability. Drug substances can be amorphous (i.e., without regular molecular lattice arrangements), crystalline (which are more oriented or aligned), polymorphic, anhydrous, or solvated. An important factor on formulation is the crys-tal or amorphous form of the drug substance. Many drug substances can exist in more than one crystalline form, with different lattice arrangements. This property is

22 Pharmaceutical Dosage Forms and Drug Delivery

termed polymorphism. Drugs may undergo a change from one metastable polymor-phic form to a more stable polymorpolymor-phic form. Various drugs are known to exist in different polymorphic forms (e.g., cortisone and prednisolone). Polymorphic forms usually exhibit different physicochemical properties, including melting point and solubility, which can affect the dissolution rate and thus the extent of its absorption.

The amorphous form of a compound is always more soluble than a corresponding crystal form. Changes in crystal characteristics can influence bioavailability and sta-bility and thus can have important implications for dosage form design. For example, insulin exhibits a differing degree of activity depending on its state. The amorphous form of insulin is rapidly absorbed and has short duration of action, while the large crystalline product is more slowly absorbed and has a longer duration of action.

TABLE 2.3