UDCA Particle Size Distribution (D90) and Tabletability
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Particle size is the one UDCA parameter the pharmacopoeia does not define. Neither the Ph. Eur. monograph (1275) nor the USP ursodiol monograph sets a D10, D50 or D90. That absence is not an oversight — particle size is a material attribute tied to a specific dosage form, and a monograph has to cover every use of the substance.
The consequence for buyers is practical and easy to miss. Because no monograph fixes the number, particle size is a supply-agreement parameter rather than a compliance parameter. Two suppliers can both ship fully compliant UDCA and still deliver material that behaves completely differently under a tablet press.
This guide explains what D10, D50 and D90 mean, why D90 is the figure that gets specified, how micronisation changes the powder, and what a particle size certificate should show. Values that follow come from published formulation work, not from a monograph, because the monograph is silent.
The monograph does not define particle size
The UDCA monograph defines chemical identity, purity and the lettered impurities. It says nothing about how fine the powder is. The same is true of the USP ursodiol monograph.
This is normal. A pharmacopoeial monograph has to describe a substance that may end up in a capsule, a tablet, a suspension or an oral solution, and a single particle size specification could not serve all of them. Particle size is therefore left to the specification agreed between buyer and seller, and to the pharmaceutical development programme that justifies it.
The practical implication is that “pharmacopoeial grade” does not answer a particle size question. If your process needs a particular D90, that requirement has to be written into your own specification, because nothing upstream will enforce it for you.
What D10, D50 and D90 actually mean
Particle size is reported as a distribution, summarised by a few percentiles. Each percentile states the size below which a given fraction of the particles falls.
| Parameter | Meaning | Typical role |
|---|---|---|
| D10 | 10% of particles are smaller than this size | Fines — relevant to flow, dusting and content uniformity |
| D50 | 50% are smaller — the median | The central tendency of the distribution |
| D90 | 90% are smaller than this size | The coarse tail — the figure most often specified |
| Span | (D90 − D10) ÷ D50 | Width of the distribution; a narrow span means more uniform particles |
Reading any one of these without the others is risky. A material can share a D50 with another batch while its D90 differs by a factor of three, and it is the coarse tail that usually decides how completely the material dissolves.
Why D90 is the number that gets specified
UDCA is poorly soluble in water, and its absorption depends strongly on how fast, and how completely, it dissolves. In a low-solubility API, dissolution is driven by surface area, and surface area is driven by the coarse end of the distribution.
A large particle sitting in a tablet is a large particle that has to dissolve from the outside in. The fraction of the material above the D90 ceiling is precisely that fraction which is slowest to dissolve — which is why D90, rather than the median, is the parameter most commonly written into a specification for a poorly soluble material.
The flow problem: UDCA powder does not compress well on its own
Before particle size can be tuned for dissolution, it has to be workable on a press. Unmilled UDCA powder has poor flow characteristics, which shows up directly in its measured flow indices.
| Parameter | Typical value for unmilled UDCA | Interpretation |
|---|---|---|
| Bulk density | ≈0.38 g/mL | Low — the powder is bulky relative to its mass |
| Tapped density | ≈0.68 g/mL | The gap between bulk and tapped density is the flow problem |
| Compressibility index | ≈45% | Well above the range associated with good flow |
| Hausner ratio | ≈1.8 | Confirms poor flow |
Numbers like these are the reason UDCA tablets are typically made from granulated rather than direct-compressed powder. The particle size specification and the manufacturing process are chosen together, not independently — a change to one can invalidate the other.
Micronisation: what it does, and what it costs
Micronisation reduces particle size to improve dissolution, and it is normally done by air jet milling — a technique that consistently produces fine, controlled distributions.
The benefit is measured against a clear reference point. Published formulation work reports that micronising UDCA to a D90 below 25 µm produces a dissolution profile matching that of an established reference tablet, which is the practical target micronisation is aiming at. Other work describes controlling material to a D90 of 30 µm or below with a D50 of 10 µm or below, and notes that coarser material does not dissolve completely within the test window.
The cost side is equally real. Micronisation adds a processing step, reduces yield, and produces finer material with more surface area — which tends to mean more electrostatic behaviour, poorer flow, and greater sensitivity to moisture. It also raises the fraction of fines, which affects content uniformity during tabletting. A supplier who can mill to a target and also hold the distribution steady batch to batch is solving a harder problem than the D90 figure alone suggests.
How particle size is measured
Particle size is measured by laser diffraction, and the method has to be reported alongside the numbers, because different dispersion methods give different results.
- Wet dispersion suspends the sample in a liquid and can apply ultrasound to break up agglomerates. Whether ultrasound is used, and for how long, changes the measured distribution.
- Dry dispersion uses an air stream. It is faster and closer to how the powder behaves in a process, but dispersion pressure matters.
Because the measurement conditions affect the result, a particle size figure is only meaningful when the method is named: instrument, dispersion mode, and any pre-treatment. A supplier who reports “D90 = 20 µm” without stating the method has given a number that cannot be reproduced or compared.
Particle size, dissolution and content uniformity
It is worth being precise about what particle size does and does not control, because it is easy to over-attribute.
For a poorly soluble API, particle size can influence dissolution — but the relationship is formulation-dependent. Wetting agents, granulation, compression force, agglomeration and crystal surface properties can each dominate the outcome. Two batches with the same D90 can still differ in dissolution if one agglomerates and the other does not.
This is why a particle size specification should be justified by the dosage form and the manufacturing route, rather than adopted from a catalogue. The number matters; the reasoning behind it matters more.
Reading a particle size certificate
- Check all three percentiles are reported. D10, D50 and D90 together describe a distribution; one alone does not.
- Check the method is named. Instrument, dispersion mode and pre-treatment — without these the numbers are not comparable.
- Check whether values are per batch or a range. A single figure is a data point; a batch-to-batch range shows process control.
- Check the span. A narrow distribution is easier to work with than a wide one with the same D90.
- Check the relationship to your process. If your tablet press needs a particular D50, say so — the monograph will not.
- Check the linkage to the impurity panel. Milling changes surface area, not chemistry, so the related substances should be unchanged.
Questions buyers ask
Does the pharmacopoeia specify a UDCA particle size?
No. Neither the Ph. Eur. nor the USP monograph sets a particle size distribution. It is agreed between supplier and buyer.
What does D90 mean?
It is the size below which 90% of the particles fall. It describes the coarse end of the distribution, which is the fraction slowest to dissolve.
What D90 should UDCA have for a tablet?
Published formulation work points to a micronised D90 below about 25 µm for dissolution matching an established reference, with other work controlling to 30 µm or below. The right target depends on the formulation.
Why is micronised UDCA harder to handle?
More surface area means more electrostatic behaviour, poorer flow and greater moisture sensitivity, and a higher fines fraction affects content uniformity.
How is particle size measured?
By laser diffraction, in wet or dry dispersion. The method and its conditions must be reported, because they change the result.
Can particle size be written into our specification?
Yes — and for a poorly soluble API it usually should be. It will not come from the monograph, so it has to come from your own acceptance criteria.
What to ask a supplier about particle size
Because no monograph fixes this attribute, the questions here are more open than for the impurities — and more revealing. A supplier who can only quote a single D90 figure, with no method and no distribution, is telling you something about how closely they control milling.
Ask for D10, D50 and D90 together, with the method named and a batch-to-batch range rather than a single value. Ask whether the material can be milled to a target tied to your dosage form. And ask whether the impurity panel is unchanged by milling, since a change in surface area should not change the chemistry.
Particle size sits alongside the rest of the specification, so it is worth reading together with the full UDCA specification. The general discipline of checking a bile-acid supplier against its own numbers is set out in how to verify a bile-acid supplier. Our ursodeoxycholic acid grade is described with the parameters buyers ask about most, and if you have a particle size target tied to your process you can request a quotation against your own acceptance criteria.
Particle size is not a pharmacopoeial parameter for ursodeoxycholic acid; it is agreed between buyer and seller. The measurement itself follows a general method — laser diffraction, described in compendial general chapters published by the European Pharmacopoeia and the United States Pharmacopeia — and the principle that acceptance criteria should be justified by the intended use is set out in the ICH quality guidelines.
This article describes pharmacopoeial requirements, material attributes and analytical interpretation only. It is not a statement of therapeutic use, and it does not set out commercial guarantees. Acceptance criteria should be justified by your own dosage form and process.
Frequently asked questions
Why does D90 matter more than an average particle size?
Because the problems arrive with the coarse tail. Flow behaviour, blending uniformity and dissolution all track the upper decile more closely than the median. A lot can sit perfectly on an average and still jam a hopper, which is why specifications written by people who run equipment quote D90 and often D10 with it.
Do different measurement methods give different D90 values?
Yes, and by amounts that matter. Laser diffraction and sieving do not agree, and dispersion conditions change laser results on their own. A D90 without a method named is a number without a context. The method line belongs next to the result on every certificate where particle size appears.
Is "white crystalline powder" a particle size control?
No. It is an appearance description, and appearance has never predicted a distribution curve. If a downstream process depends on flow or tabletability, the specification needs a measured line with a method. Everything else is hope with a chemical name attached.
What happens at the tablet press when D90 drifts?
Weight uniformity and dissolution move with it, usually quietly. The drift shows up as an adjustment at the press long before it shows up as a failed specification, and the cost is absorbed as inefficiency rather than recorded as a defect. That is exactly why it goes unnoticed: nothing fails, everything gets worse.
Should micronised and crystalline material share one specification?
No. They come from different processes with different distributions and different variability. A single specification covering both forces one of them to be tested against limits it was never designed to meet. Two products, two lines.
What should a buyer confirm about PSD on every lot?
Method, dispersion conditions, and whether the material was tested as produced or after any milling step. The third point decides whether the certificate describes the drum that ships or the powder inside it. All three questions take the supplier less than a minute to answer and take months to reconstruct after a dispute.