In the process of small molecule drug development, lipophilicity (or hydrophobicity) is a very important indicator that has a crucial impact on pharmacokinetics and pharmacodynamics. Lipophilicity involves the pharmacokinetic processes of absorption, distribution, metabolism, and excretion of drugs in the body. The well-known Lipinski’s Rule of Five for small molecule oral drug design (which has been increasingly challenged) suggests that the lipophilicity of rational small molecule oral drugs should meet the rough requirement of a partition coefficient LogP not exceeding 5.
The importance of lipophilicity in small molecule drugs can be reflected in several aspects:
Absorption Performance: Lipophilicity plays a crucial role in the absorption of drugs in the gastrointestinal tract. Generally, drugs require sufficient lipophilicity to cross biological membranes, such as the gastrointestinal mucosa. However, excessive lipophilicity may also lead to poor solubility in aqueous environments, thus affecting dissolution and absorption.
Distribution Performance: Lipophilicity influences the distribution of drugs in the body. Drugs with higher lipophilicity are more likely to penetrate cell membranes and enter cells or fatty tissues. This may be beneficial for drugs that need to act within target cells, but for other drugs, especially those that need to maintain high concentrations in the bloodstream, it may lead to uneven distribution.
Drug Metabolism: The lipophilicity of drugs can also affect their metabolism. Drugs with higher lipophilicity usually pass through the liver’s metabolic enzyme system more easily, leading to the formation of metabolites that are more easily excreted. This may also affect the drug’s half-life and clearance rate in the body.
Drug Target Affinity: The lipophilicity of drugs may affect their affinity for targets. Some targets may be more easily targeted by drugs in a lipid environment. Moderately lipophilic drugs typically interact more easily with membrane proteins or other lipid structures.
Solubility: The solubility of drugs in water is usually related to their lipophilicity. Drugs with higher lipophilicity may have lower solubility in water, which may limit their suitability for oral administration.
Due to the hydrophobic nature of many protein binding pockets, increasing the lipophilicity of ligands (drugs) typically enhances their affinity with the target, but it may also increase the risk of off-target effects. In drug design, researchers often modulate the lipophilicity of drugs by adjusting the molecular structure or introducing/modifying specific chemical groups to optimize their performance in vivo. This requires a balanced approach within a reasonable range to ensure that the drug reaches appropriate concentrations in the body and can interact effectively with the target.
There seems to be a perception in the pharmaceutical industry that today’s drugs are different from those of the past few decades, with one aspect being the increase in drug molecular weight and lipophilicity. This appears to be an inevitable phenomenon as understanding of receptors and disease models deepens. Data is the best means of validating such a perception.
In a study conducted by Nanoform, it was found that the lipophilicity of drugs, characterized by LogP (partition coefficient), indeed showed a trend of continuous increase among approved drugs.
Lipids at BOC Sciences
| Branched Lipid | Branched-chain lipids are a unique class of lipids that play a crucial role in various biological processes. These lipids contain branching points in their hydrocarbon chains, which distinguish them from more common linear lipids. |
| Cationic Lipid | Cationic lipids are a class of lipids with positively charged head groups that have been widely studied and exploited due to their ability to form complexes with negatively charged molecules such as nucleic acids, proteins, and other biomolecules. |
| Natural Lipids | Natural lipids are a class of complex biomolecules present in the bodies of plants and animals or in their products. |
| Ionizable Lipid | Ionizable lipids are lipid compounds containing ionizable functional groups (such as amines, carboxylates or guanidine groups). |
| Phospholipids | Phospholipids are amphiphilic lipids consisting of a glycerol backbone or an amino-alcohol sphingosine backbone, including two hydrophobic “tails,” which are fatty acid chains, and one hydrophilic “head,” which is phosphate group. |
This research indicates that the average and median LogP values of approved drugs from 1990 to 2021 seemed to increase over time. Over the past twenty years, the average and median LogP values have increased by one unit. Due to the logarithmic nature of the partition coefficient LogP, an increase of one unit actually represents a tenfold increase in the lipophilicity of the latest drugs compared to those in the past.
After confirming the trend of increasing lipophilicity in small molecule drugs, the next related question is why this phenomenon is occurring.
As mentioned earlier, with the deepening understanding of receptors and disease patterns, it is inevitable that people will design larger small molecule drugs from scratch to bind more effectively and specifically with the target. This to some extent leads to an inevitable increase in lipophilicity.
Before analyzing this issue further, we need to carefully examine the details of the changes in drug LogP. From Figure 1, it can be observed that the category of small molecule drugs that violate Lipinski’s Rule of Five, i.e., those with LogP greater than 5, actually remained relatively constant, or even showed a slight decrease. This indicates that drug designers did not endlessly increase the lipophilicity of small molecule drugs during the process of drug discovery. Therefore, the year-over-year increase in the median and mean LogP of drugs is not contributed by this part.
On the other end, there was a decrease in the number and proportion of highly polar molecules (LogP < 0), which was most noticeable by 2010. This suggests that the main driving factor for the overall increase in drug lipophilicity is actually the decrease in the proportion of highly polar molecules. Upon careful examination of the structures of highly polar drugs approved from 1970 to 2021, especially their hydrophilic structures, drug designers can easily find that they are mainly natural products or derivatives of natural products (Figure 2). For example, gentamicin approved in 1970 is a natural product, while cephaloglycin (cephalosporin III) is a derivative of the natural compound cephalosporin C.
Many biologically active natural compounds possess highly hydrophilic characteristics because most biochemical processes inside cells and organisms occur in aqueous media. Highly hydrophilic compounds are typically more soluble in water, which is a prerequisite for absorption, distribution, and interaction with biomolecules in the body.
In the process of drug discovery, mimicking nature is a key approach. From 1981 to 2010, approximately 50% of FDA-approved new drugs were related to natural products (e.g., semisynthetic analogs). However, issues related to synthetic difficulty, purification, and off-target toxicity led many pharmaceutical companies to reduce their natural product drug discovery programs in the 1990s and early 2000s, turning instead to more modern targeted drug discovery. This change in drug discovery approach resulted in an increase in the median LogP.
Although the approach of directly deriving drugs from natural compounds has gradually receded, the diversity and complexity of synthetic drugs continue to grow. This can be easily seen from the contrast in complexity of synthetic drug molecular structures between 1970 and 2021 as shown. It is visually evident that today’s fully synthetic molecules are often more complex than those from the 1970s. For example, Sotorasib, approved in 2021, is one such drug synthesized as a configurationally stable isomer.
Although natural products are no longer the primary inspiration for complex molecular structures in drugs, today’s candidate drugs have reached a considerable level of sophistication, especially with the use of artificial intelligence, which can create molecules with unique physicochemical properties. The increase in lipophilicity, the increase in aromatic ring numbers, and related properties increase molecular bioactivity, but also pose challenges for solubility and bioavailability. Therefore, in the context of increasing molecular structural complexity and lipophilicity, ensuring that drug molecules have sufficiently good pharmacokinetic properties has become a new challenge facing drug developers.
Nanoemulsions
For highly hydrophobic drug molecules, it may be difficult to formulate them into tablets because they need to break down into very small crystals to be absorbed by the body. To achieve acceptable bioavailability of hydrophobic drugs, pharmaceutical companies typically need to use special processes to grind compounds into nanocrystals, which are more easily absorbed by human cells. These crystals are then mixed with excipients. One common excipient often mixed with hydrophobic drugs is methylcellulose. Methylcellulose is water-soluble and helps the drug release more quickly in the body. However, this method is relatively inefficient and may introduce new problems during the grinding process.
To address this issue, researchers have studied a more efficient method of combining hydrophobic drugs with methylcellulose by forming emulsions. When the diameter of these droplets reaches the nanometer scale, this mixture is called a nanoemulsion. Ultrasonic waves can generate nanoscale oil droplets. Methylcellulose helps prevent water droplets and oil droplets from separating (layering) because it is amphiphilic and can bind with both oil droplets and water. Once the emulsion is formed, researchers can convert it into a gel by dripping the liquid into a hot water bath. As each droplet falls into the water, it solidifies within milliseconds. Researchers can control the size of the particles. Particle formation is almost instantaneous, so all substances in the droplets are converted into solid particles without any loss. After drying, drug nanocrystals uniformly distributed in a methylcellulose matrix are obtained.
Types of Nanoemulsions at BOC Sciences
Lipid-Based Drug Delivery Systems (LBDDS)
LBDDS (Lipid-based drug delivery systems) is a general term referring to drugs dissolved or suspended in lipid excipients. Lipid substances are typically esters of fatty acids, which are esters connecting fatty acids with hydrophilic groups such as glycerol, polyglycerol, or polyols (note the difference between esters and lipids, the former refers to the chemical structure formed between acids and alcohols, while the latter refers to a general term for structures containing long carbon chains). In addition to conventional lipids, hydrophobic polymers can be used as similar excipients. The melting point, solubilization capacity, and miscibility of excipients are determined by the chain length and unsaturation of fatty acids.
Drug-loaded micelles are a manifestation of LBDDS applications. Researchers have developed drug-loaded micelles to deliver highly lipophilic drugs, taking advantage of the high solubility of drugs in certain micelles (<1 µm) and their high solubility in solvents.
Amphiphilic diblock copolymers composed of hydrophilic segments (such as polyethylene glycol PEG) and hydrophobic segments (alkyl chains, polylactic acid PLA, or polyglycolic acid PGA) have the ability to form micelles. Hydrophobic drugs can be surrounded by the hydrophobic segments inside the micelles, while the hydrophilic PEG segments are exposed to the hydrophilic solvent. PEG is commonly used as a biocompatible hydrophilic polymer, while PLA and PGA degrade into their corresponding carboxylic acids over time and can be safely metabolized from the body.
In summary, the hydrophobicity of drugs inevitably increases with the increasing complexity of drug chemical structures. To address this phenomenon, researchers have developed various delivery strategies to assist in the formulation process of hydrophobic drugs, maximizing the biological advantages of hydrophobic drugs.