Cannabinoid Solubility and Absorption: From Formulation to Measured Bioavailability

By Cannible Editorial

2026-07-31

The central distinction is simple: poor aqueous solubility can be a formulation challenge, but faster dissolution or greater drug exposure does not by itself demonstrate greater human bioavailability. In the supplied evidence, a laboratory formulation released more than 90% of its CBD within 15 minutes, while its in vivo study reported 27% oral bioavailability without identifying the species. Separately, a controlled human pharmacokinetic study measured substantially higher CBD plasma exposure when a pharmaceutical CBD oral solution was taken with food, milk, or alcohol; it did not establish the fraction of a dose reaching human circulation. 1 2

This article is general information, not individualized medical, dosing, safety, or legal advice. A personal decision about a cannabinoid product, formulation, route, or interaction should be discussed with a clinician, pharmacist, or other qualified professional.

Laboratory solubility: what dissolves in a test system

Laboratory evidence identifies CBD as having poor aqueous solubility and low oral bioavailability, which motivated development of a nanostructured lipid carrier formulation. In this context, solubility refers to behavior in an aqueous test environment; it is not a measurement of how much CBD enters human blood after a dose. 1

For the most promising tested formulation, called NLC5, laboratory characterization reported 99.23% CBD entrapment efficiency, a particle size of 207 nanometres, a polydispersity index of 0.19, and a zeta potential of −26 millivolts. These are formulation and laboratory measurements, not human absorption measurements. 1

Drug-release testing found that more than 90% of CBD was released within 15 minutes from NLC5, described as an improvement in dissolving rate compared with pure CBD. That result shows enhanced release under the study’s testing conditions; it does not show that a person absorbed 90% of the dose or that the formulation improved demonstrated human bioavailability. 1

Formulation science: changing the delivery system

Formulation science uses physical and chemical design to address properties such as poor aqueous solubility. In the cited study, researchers developed nine CBD nanostructured lipid carrier formulations using a conventional hot-homogenization method, and NLC5 was selected as the most promising based on its laboratory characteristics and release testing. 1

The formulation was also evaluated for stability at 4 °C and 25 °C over three months, with consistent reported parameters. This is stability evidence for the tested formulation under those conditions, not evidence that the product produces a particular clinical effect or exposure in people. 1

The study’s in vivo pharmacokinetic evaluation of NLC5 reported 27% CBD oral bioavailability. The supplied evidence does not identify the species, dosing conditions, comparator, or other experimental details needed to interpret that number fully. It therefore cannot be presented as demonstrated human bioavailability. More broadly, an in vitro release result and an in vivo exposure result answer different questions, and neither should be merged with controlled human evidence. 1

Pharmacokinetics: what was measured in people

Controlled human evidence is available for a plant-derived pharmaceutical formulation of highly purified CBD administered as a 100-milligram-per-millilitre oral solution. In a phase 1 randomized pharmacokinetic trial, healthy adults received a single 750-milligram dose in one of several conditions: fasted, with a high-fat/high-calorie meal, with a low-fat/low-calorie meal, with whole milk, or with alcohol. Blood samples were collected through 96 hours, and CBD and major metabolites were quantified using liquid chromatography with tandem mass spectrometry. 2

Compared with the fasted state, the high-fat/high-calorie meal increased CBD exposure 3.8-fold by area under the concentration-time curve and 5.2-fold by maximum observed plasma concentration. A low-fat/low-calorie meal increased those measures 2.7-fold and 3.8-fold, respectively. These are controlled human pharmacokinetic findings for the tested pharmaceutical oral solution and conditions; they are not a universal result for every CBD product or meal. 2

Whole milk increased CBD exposure 2.4-fold by area under the curve and 3.1-fold by maximum concentration. Alcohol produced smaller increases of 1.6-fold and 1.9-fold, respectively. The trial reported no clinically relevant change in CBD time to maximum concentration or half-life for the tested conditions compared with fasting, although the metabolite 7-carboxy-CBD reached its maximum concentration later when CBD was administered with alcohol. 2

The study reported moderate to high variability between and within subjects. CBD was tolerated in the trial, with no severe or serious adverse events reported. These findings describe exposure under a specific controlled study design; they do not establish that an over-the-counter or otherwise different cannabinoid formulation behaves in the same way. 2

Route of administration: a separate variable

Route-of-administration evidence indicates that the pharmacokinetics and observed effects of cannabinoids depend on both formulation and route. The supplied material does not provide a comparative human dataset for specific routes, such as inhalation, oral, or other administration methods, and it does not support assigning a bioavailability value to those routes here. 3

The human trial described above was an oral study of a specified CBD solution, with exposure compared across fed, fasted, milk, and alcohol conditions. Its results should therefore be kept separate from laboratory release testing, the unidentified-species in vivo formulation study, and any conclusions about other routes or products. 2 1 3

Demonstrated human bioavailability: what the evidence does and does not show

Demonstrated human bioavailability means that a study in people measures the proportion of an administered dose that reaches systemic circulation, or otherwise provides a validated human bioavailability comparison. The supplied evidence reports human CBD pharmacokinetic exposure measures, including maximum concentration and area under the curve, but it does not report an absolute human bioavailability percentage for the tested oral solution. 2

Accordingly, the strongest human conclusion supported here is conditional: in healthy adults receiving a single 750-milligram dose of the specified pharmaceutical CBD oral solution, food, whole milk, and alcohol increased measured plasma exposure relative to fasting, with the largest increases after a high-fat/high-calorie meal. This is controlled human pharmacokinetic evidence, not proof that the same exposure changes occur with a different formulation, cannabinoid, dose, population, or route. 2

The 27% oral bioavailability figure belongs to the NLC5 in vivo study, but the supplied evidence does not identify the species. It must therefore remain an in vivo formulation-study result of unspecified species rather than a demonstrated human result. No evidence supplied here establishes that NLC5, or any other formulation described, improves bioavailability in people. 1

Why exposure and safety cannot be inferred from solubility alone

Pharmacokinetic evidence also shows that exposure can be altered by metabolism and interactions, not only by dissolution. CBD is metabolized primarily in the liver and gut by CYP2C19, CYP3A4, and several UGT enzymes. In healthy subjects, coadministration with clobazam increased exposure to the active CBD metabolite 7-OH-CBD and also increased exposure to clobazam’s active metabolite, N-desmethylclobazam, by approximately threefold for both maximum concentration and area under the curve. 4

The supplied evidence further reports higher CBD exposure in people with moderate or severe hepatic impairment than in healthy subjects, and describes potential pharmacokinetic drug interactions through enzymes or transporters. These are human pharmacokinetic and clinical-evidence considerations, not conclusions that can be predicted from a laboratory dissolution profile alone. 4 3

The practical evidence hierarchy is therefore: laboratory solubility and release testing describe test-system performance; formulation science describes how a delivery system is engineered; pharmacokinetics measures concentrations and exposure over time; route-of-administration evidence compares how delivery method and formulation affect those measurements; and demonstrated human bioavailability requires a substantiated study in people. The supplied record supports some conclusions at each earlier level, but it does not supply a human bioavailability percentage for the formulations discussed. 1 2 3