Which factor typically has a negative impact on drug solubility?

In the context of drug solubility, increased crystallinity negatively impacts the solubility of a drug because crystalline drug forms are generally more ordered and stable compared to their amorphous counterparts. This crystalline structure means that the molecules are tightly packed, making it more difficult for solvent molecules to access and interact with the drug molecules. Consequently, the energy required to break the intermolecular forces in a crystal lattice is higher, which results in lower solubility.

On the other hand, increased temperature typically enhances solubility by providing energy that helps to break intermolecular forces within the solute. Decreased hydrophobicity generally implies that a drug is more soluble in aqueous environments, again promoting solubility. High molecular weight can have varying implications; while larger molecules might facilitate certain interactions, it doesn't universally equate to reduced solubility. In many cases, it is the crystalline nature of the drug that is a more significant barrier to solubility than the other factors listed.