Methods and apparati for nondestructive detection of undissolved particles in a fluid
The apparati, methods, and computer program products disclosed herein can be used to nondestructively detect undissolved particles, such as glass flakes and/or protein aggregates, in a fluid in a vessel, such as, but not limited to, a fluid that contains a drug.
1. A method of nondestructive counting and sizing of undissolved particles in a vessel that is at least partially filled with a fluid, the method comprising:
(a) receiving, by a sensor of an imaging system, at least one image of the particles in the vessel obtained under specified imaging conditions; and analyzing the at least one image by a processor of the imaging system, the analyzing including (b)-(d):
(b) detecting the particles and determining information indicative of an apparent size of the detected particles in the image;
(c) determining apparent particle size population information indicative of an apparent particle size distribution of the detected particles; and
(d) determining actual particle size population information indicative of an actual particle size distribution of the detected particles based on:
(i) the apparent particle size population information; and
(ii) calibration population information indicative of the apparent size distribution of one or more sets of standard sized particles imaged under conditions corresponding to the specified imaging conditions;
wherein (d) comprises fitting a superposition of apparent size distributions for a plurality of the sets of standard sized particles to the apparent particle size population of the detected particles; and
wherein fitting the superposition of apparent size distributions for the plurality of sets of standard sized particles conditions to the apparent particle size population of the detected particles comprises: minimizing a difference between the superposition and the apparent particle size population of the detected particles by adjusting the weighting of the apparent size distributions for the plurality of sets of standard sized particles.
2. A method of nondestructive counting and sizing of undissolved particles in a vessel that is at least partially filled with a fluid, the method comprising:
(a) receiving, by a sensor of an imaging system, at least one image of the particles in the vessel obtained under specified imaging conditions; and analyzing the at least one image by a processor of the imaging system, the analyzing including (b)-(d):
(b) detecting the particles and determining information indicative of an apparent size of the detected particles in the image;
(b1) selecting a first set of particles for counting based on the apparent size of the particles;
(c) determining apparent particle size population information indicative of an apparent particle size distribution of the first set of particles; and
(d) determining actual particle size population information indicative of an actual particle size distribution of the first set of particles based on:
(i) the apparent particle size population information; and
(ii) calibration population information indicative of the apparent size distribution of one or more sets of standard sized particles imaged under conditions corresponding to the specified imaging conditions.
3. The method of claim 2 , wherein the particles in the first set of particles are selected based on an apparent size threshold.
4. The method of claim 2 , wherein the at least one image comprises a time-series of images, and comprising:
detecting or counting particles of a second set of particles different from the first by determining trajectories of the second set of particles based on the time-series of images.
5. An apparatus for counting and sizing undissolved particles in a vessel that is at least partially filled with a fluid, the apparatus comprising a memory and at least one processor configured to execute instructions from the memory, the instructions when executed configuring the processor to:
(a) receive from the memory at least one image of the particles in the vessel obtained under specified imaging conditions;
(b) based on the at least one image, detect the particles and determine information indicative of an apparent size of the detected particles in the image;
(c) determine apparent particle size population information indicative of an apparent particle size distribution of the detected particles; and
(d) determine actual particle size population information indicative of an actual particle size distribution of the detected particles based on:
(i) the apparent particle size population information; and
(ii) calibration population information indicative of the apparent size distribution of one or more sets of standard sized particles imaged under conditions corresponding to the specified imaging conditions;
wherein the instructions when executed further configure the processor to fit the superposition of apparent size distributions for the plurality of sets of standard sized particles to the apparent particle size population of the detected particles by: minimizing a difference between the superposition and the apparent particle size population of the detected particles by adjusting the weighting of the apparent size distributions for the plurality of sets of standard sized particles.
6. An apparatus for counting and sizing undissolved particles in a vessel that is at least partially filled with a fluid, the apparatus comprising a memory and at least one processor configured to execute instructions from the memory, the instructions when executed configuring the processor to:
(a) receive from the memory at least one image of the particles in the vessel obtained under specified imaging conditions;
(b) based on the at least one image, detect the particles and determine information indicative of an apparent size of the detected particles in the image;
(c) determine apparent particle size population information indicative of an apparent particle size distribution of the detected particles; and
(d) determine actual particle size population information indicative of an actual particle size distribution of the detected particles based on:
(i) the apparent particle size population information; and
(ii) calibration population information indicative of the apparent size distribution of one or more sets of standard sized particles imaged under conditions corresponding to the specified imaging conditions;
wherein the instructions when executed further configure the processor to preprocess the at least one image to select a first set of particles for counting based on the apparent size of the particles, wherein (c) and (d) is applied only to the first set of particles.
7. The apparatus of claim 6 , wherein the particles in the first set of particles are selected based on an apparent size threshold.
8. The apparatus of claim 7 , wherein the at least one image comprises a time-series of images, and wherein the processor is configured to detect or count particles of a second set of particles different from the first by determining trajectories of the second set of particles based on the time-series of images.