Crystallinity, Solid State Manipulations, and Solubility

Practice flashcards covering the effects of crystallinity, solid state forms, cosolvents, solubilisation, complexation, and temperature on drug solubility based on the SoM1 lecture.

How does molecular symmetry affect the solubility of alanine compared to 2-amino butyric acid?

Alanine is less soluble ($1.66\,mol/L$) because its symmetrical molecules form a compact crystal with a high melting point ($295^\circ\text{C}$), whereas 2-amino butyric acid packs less efficiently, has a lower melting point ($195^\circ\text{C}$), and is more soluble ($1.8\,mol/L$).

How do the dissolution properties of the amorphous and crystalline forms of Novobiocin differ?

The crystalline form dissolves very slowly and is inactive, whereas the amorphous form is more soluble, rapidly dissolves, and is readily absorbed.

According to the Van’t Hoff relationship, what three factors determine the solubility of a solid in an ideal solution?

Temperature ($T$), the melting point of the solute ($T_m$), and the molar heat of fusion ($\Delta H_f$).

What is the general relationship between the melting point of sulpha-compounds and their aqueous solubility?

In general, a lower melting point results in higher solubility; for example, S’thiazole ($173-175^\circ\text{C}$) has a solubility of $0.588\,mg/100\,mL$, while S’diazine ($252-256^\circ\text{C}$) has a lower solubility of $0.077\,mg/100\,mL$.

Define a 'eutectic composition'.

The specific mixture of two crystalline solids that results in the lowest possible melting point, which may even cause the solids to become liquid at certain temperatures.

What is a pharmaceutical example of a beneficial eutectic mixture?

The mixture of lidocaine and prilocaine (EMLA), which is liquid at room temperature, enhancing dissolution rate and absorption.

How can the solubility of hydrocortisone be chemically modified to make it water-soluble?

By creating a prodrug derivative such as hydrocortisone sodium phosphate, which is freely soluble compared to the practically insoluble parent drug.

What is a 'cosolvent' and how does it affect solubility?

A cosolvent is a water-miscible solvent added to a vehicle to increase the solubility of weak electrolytes and non-polar compounds by altering the polarity of the solvent system.

What are common pharmaceutical examples of cosolvent use?

Paracetamol elixir uses ethanol and propylene glycol; Betnovate scalp application uses isopropyl alcohol; Nitroglycerin Spray uses glycerol and ethanol.

In the simple model for cosolvent solubility, what does the formula $\ln(S_f) = \ln(S_0) + f\sigma$ represent?

$S_f$ is the solubility in the mixed solvent, $S_0$ is the solubility in water, $f$ is the volume fraction of the cosolvent, and $\sigma$ is the system constant.

How does the addition of ethanol affect the pKa of phenobarbitone?

Increasing the amount of ethanol increases the pKa value; for example, the pKa of phenobarbitone in water is $7.41$, but in $30\%$ ethanol, it increases to $7.92$.

What is the core principle behind the use of 'solubility parameters'?

The principle 'like dissolves like', meaning the closer the solubility parameter ($\delta$) of the solute and solvent, the more the system exhibits ideal behavior and higher solubility.

At what solvent ratio is the maximum solubility of caffeine reached in a dioxan/water mixture?

Maximum solubility occurs at $28\%$ water and $72\%$ dioxan.

How do surfactants improve the solubility of poorly water-soluble drugs?

Surfactants form micelles (hydrophobic interior and hydrophilic exterior) where non-polar drug molecules can dissolve within the hydrophobic interior.

What is Lysol and how does it demonstrate solubilisation?

Lysol is a formulation of cresol using potassium soaps of oleic, linoleic, and linolenic acids, which increases the aqueous solubility of cresol from $2\%$ to $50\%$.

What is a potential detriment of molecular complexation regarding bioavailability?

Complexation may be detrimental if it creates an insoluble complex, such as when tetracycline forms an insoluble complex with calcium carbonate, leading to slower dissolution.

Describe the structure and solubility properties of cyclodextrins.

Cyclodextrins are hollow cylindrical glucose units with a hydrophobic interior (allowing poorly soluble drugs to insert) and a hydrophilic exterior (making the entire complex water-soluble).

Distinguish between $\alpha$, $\beta$, and $\gamma$ cyclodextrins.

$\alpha$-cyclodextrin contains 6 glucose units, $\beta$-cyclodextrin contains 7 units, and $\gamma$-cyclodextrin contains 8 units.

How does temperature affect the solubility of endothermic versus exothermic reactions?

In endothermic reactions (e.g., $Na_2SO_4 \cdot 10H_2O$), increased temperature increases solubility; in exothermic reactions (e.g., $Na_2SO_4$), increased temperature decreases solubility.