I am currently working on a stability indicating method for Doxycycline and do not know what else to try:

Things I have tried
* Column packings - C8, C18, CN, Phenyl, and Phenyl-hexyl (all dimensions and particle sizes)
The smaller the dimensions/ particle size the worse the peak shape gets - Have concluded that 5u particle size works best.
*Mobile phases
1. A - 25mM NaH2PO4 + 6g Pentanesulfonate sodium + 2.25g NaOH in 3 L of H2O, pH adjust to 7.0 with H3PO4; B - ACN (This mobile phase worked really well with a C18 column, but could not resolve the degradants as well as having the issue of the buffer precipitating out when the organic % became to high.
2. A - 0.1% TFA/ 1% ACN/ H2O; B - 0.1% TFA/ACN (This works well on C18, CN, C8, and Phenyl, but still have an issue with fronting and resolution)
3. A - Nanopure Water; B - ACN; C - THF (Did not work at all on C8 column - which was described in an article that I found)
4. A - 20 mM Ammonium phosphate, ph 2.5; B - ACN (Works well on Phenyl, C8, and C18 but still can not get resolution nor get rid of the fronting)
5. A - 10 mM Potassium phosphate, monobasic; B - 1% THF/ACN (Does not work with the C8 column currently using)

I have tried different flowrates, gradients (shallow and steep), and different column temperatures and still have trouble reducing the fronting and getting the resolution needed. I have tried to research different methods online and there are very few to choose from.

Please HELP, I am open to any suggestions.